TUGAS MATA KULIAH IMUNOLOGI

MEMBUAT JURNAL SALAH SATU PENYAKIT AUTOIMUN

“MYASTHENIA GRAVIS”

Nama Kelompok:
Annisa Widya Maharani (182210101010)
Erlik Fiana Sari (182210101013)
Lintang Qonita Fardliana (182210101016)
Wahyuni Ella Dwi Prasanti (182210101073)
Rika Ansyari (182210101138)

Nama Dosen: Ika Puspita Dewi, M.Biomed., Apt

FAKULTAS FARMASI
UNIVERSITAS JEMBER
2019
Annisa Widya Maharani 182210101010, Erlik
Fiana Sari 182210101013 , Lintang Qonita
Fardliana 182210101016, Wahyuni Ella Dwi
Prasanti 182210101073, Rika Ansyari 182210101138
Myasthenia Gravis
Apa itu sistem kekebalan tubuh?
Sistem kekebalan tubuh adalah
penyerangan atau pertahanan tubuh
terhadap infeksi atau bisa dikatakan sistem
pada tubuh yang biasanya memproduksi
protein yang disebut “antibodi”. Antibodi
berfungsi untuk membantu mencegah atau
melawan infeksi.
Abstrak
Dengan angka kejadian tahunan dari 8
sampai 10 kasus per 1 juta orang, 4
myasthenia gravis dan berbagai
subkelompoknya adalah penyakit utama
yang mempengaruhi sambungan
neuromuskuler. The Lambert- Eaton
myasthenic sindrom dan neuromyotonia
adalah presinaptik gangguan autoantibodi
yang langka ditandai dengan disfungsi otot
rangka. 5 sindrom miastenia kongenital dan
kondisi toksin (misalnya, botulism) dapat
juga mempengaruhi sambungan
neuromuskuler dan menyebabkan
kelemahan otot. Ulasan ini berfokus pada tes
baru diagnostik untuk myasthenia gravis dan
individualisasi terapi sesuai dengan
biomarker (Havlícek, 1981).
Disfungsi pada neuromuscular junction
mendasari beberapa gangguan yang ditandai
dengan kelemahan otot rangka yang
melibatkan beberapa otot tapi tidak semua
kelompok otot. Bentuk genetik dari
gangguan ini disebut sindrom miastenia
kongenital. Myasthenia gravis adalah bentuk
kelompok penyakit terbesar dari gangguan
neuromuscular junction dan disebabkan oleh
autoantibodi patogen ke komponen otot
postsynaptic. Fluktuasi keparahan
kelemahan otot yang khas. Beberapa, tetapi
tidak semua otot dipengaruhi dan tidak
selalu simetris. Peningkatan kelemahan
dengan aktivitas otot terus menerus
merupakan petunjuk diagnostik untuk
myasthenia gravis, namun gejala klinis dapat
bervariasi. Pasien dengan myasthenia gravis
harus diklasifikasikan menjadi
subkelompok, supaya bisa ditentukan yang
tepat untuk diagnosis, terapi yang optimal,
dan prognosis. Sebagai pengelompokan ini
memperhitungkan autoantibodi,
epidemiologi, klinis, dan komorbiditas.
Autoantibodi terhadap reseptor asetilkolin
(AChR), otot-spesifik kinase (Musk), dan
lipoprotein protein 4 (LRP4) sebagai
penanda diagnostik yang sensitif dan
spesifik serta menjadi faktor pathogen.
Autoantibodi ini juga sebagai salah satu
faktor untuk pengelompokan pasien
myasthenia gravis. (Gilhus dan
Verschuuren, 2015).
Myasthenia gravis adalah kondisi autoimun
neuromuscular kronis yang menyebabkan
kelemahan otot rangka tubuh. MG
disebabkan oleh kesalahan dalam transmisi
impuls saraf ke otot.
Kelemahan tersebut dapat umum atau lokal,
dan hampir selalu berdampak pada otot
mata, dengan diplopia dan ptosis. Diplopia
adalah suatu gangguan penglihatan di mana
pasien akan melihat dua gambar dari satu
objek yang berdekatan (penglihatan ganda).
Ptosis adalah istilah medis yang digunakan
untuk menyatakan turunnya
kelopak mata bagian atas sehingga tidak
dapat membuka mata sepenuhnya atau
dalam bahasa sehari-hari kita sebut sebagai
mata sipit sebelah. Pola keterlibatan
gangguan mata biasanya simetris. Artinya
jika mata kanan mengalami gangguan
seperti sipit sebelah, maka mata kiri akan
mengikutinya. Kelemahan biasanya
meningkat dengan olahraga dan penggunaan
otot berulang (kelelahan) dan bervariasi dari
hari ke hari. (Havlícek, 1981)
Myasthenia gravis merupakan penyakit
autoimun yang berhubungan dengan
antibodi terhadap reseptor asetilkolin, otot-
spesifik reseptor tirosin kinase (Musk),
terkait lipoprotein-protein 4 (LRP4), atau
Agrin dalam membran postsynaptic pada
sambungan neuromuskuler. Pasien
myasthenia gravis harus diklasifikasikan
menjadi subkelompok untuk membantu
keputusan terapi dan prognosis. Pembagian
subkelompok didasarkan pada antibodi
serum dan awal gejala klinis, akhir-onset,
thymoma, Musk, LRP4, antibodi-negatif,
dan bentuk mata dari penderita myasthenia
gravis. Agrin terkait myasthenia gravis
mungkin muncul sebagai entitas baru.
Prognosis baik dengan gejala optimal,
imunosupresif, dan pengobatan suportif.
Pyridostigmine adalah pengobatan
simtomatik yang lebih disukai. Sementara
untuk pasien yang tidak merespon secara
memadai terapi simptomatik, kortikosteroid,
azatioprin, dan timektomi dianjurkan unruk
perawatan imunosupresif. Baru-baru ini obat
imunomodulator tambahan ditemukan, tetapi
keputusan terapeutik terhambat oleh
kelangkaan studi terkontrol. Terapi obat
jangka panjang penting untuk sebagian besar
pasien dan harus disesuaikan dengan bentuk
myasthenia gravis tertentu. (Gilhus dan
Verschuuren, 2015)
Apa yang menyebabkan Myasthenia
Gravis?
MG disebabkan oleh kesalahan dalam
transmisi impuls saraf ke otot-otot. Pada
pasien MG, sistem kekebalan tubuhnya
membuat antibodi yang keliru sehingga
menyerang koneksi antara saraf dan otot
kemudian mencegah otot berkontraksi dan
mengakibatkan kelemahan. Beberapa orang
mungkin memiliki Myasthenia Gravis yang
tidak disebabkan oleh antibodi yang
menghalangi asetilkolin atau reseptor tirosin
kinase. Jenis kondisi ini disebut Myasthenia
Gravis Antibodi-Negatif. (Council for
Medical Schemes, 2014)
Siapa yang mendapat Myasthenia
Gravis?
Myasthenia Gravis terjadi pada semua
kelompok etnis dan semua jenis kelamin. Ini
paling sering mempengaruhi wanita dewasa
muda (di bawah 40) dan pria yang lebih tua
(lebih dari 60), tetapi juga dapat terjadi pada
usia berapa pun. Kondisi ini tidak diwarisi
secara langsung juga tidak menular.
(Council for Medical Schemes, 2014)
Kasus Umum
Miastema gravis adalah penyakit yang
jarang ditemui karena penyakit ini langka.
Miestenia gravis biasanya terjadi pada usia
50 tahun keatas. Pada perempuan, penyakit
ini biasanya muncul di usia sektar 30 tahun
sedangkan pada laki laki, penyakit ini
muncul di usia sekitar 60 tahun. Kondisi ini
disebabkan oleh gangguan komunikasi
antara saraf dan otot yang mana biasanya
terjadi kelemahan pada otot lengan dan kaki,
pandangan bias, serta kesulitan untuk
berbicara. Kondisi ini dapat bertaha selama
bertahun tahun hingga seumur hidup.
Anatomi dan Fisiologi Neomuscular
junction
Neomuscular junction atau synaptic
transmission adalah gangguan yang
menyebabkan salah satu karakteristik akibat
dari Miastemia gravis. Terdapat potensial
aksi pada neuron motorik dimana sewaktu
mendekati otot, akson membentuk cabang.
Dari cabang cabang tersebut akan
membentuk otot secara keseluruhan yang
mana bentuknya panjang dan silinder. Pada
Neomuscular junction ini sel otot dan sel
saraf tidak berikatan melainkan terdapat
celah antara keduanya. Celah yang ada pada
sel otot dan sel saraf ini sangat besar
sehingga memungkinkan terjadinya
transmisi suatu impuls diantara sel saraf dan
sel otot pada Neomuscular junction tersebut.
Sama seperti hal nya pada sinaps, yaitu
terdapat pembawa informasi dimana
menyambungkan antara sel saraf dan sel
otot, maka dari itu neurotransmitter disini
juga disebut sebagai Ach (Asetilkolin).
Vesikel berfungsi untuk menyimpan
membran pre sinaptik yang mengandung
Asetilkolin dimana apabila terbukanya
channel Ca+ Voltage Gated akan
menyebabkan influks kalsium. Influks
kalsium ini yaitu masuknya kalsium pada
membran dimana vesikel yang diaktifkan
oleh influks tadi akan mendocking ke tepi
membran. Sehingga setilkolin atau Ach tadi
akan dilepaskan ke celah sinaptik. Ach yang
telah dilepaskan ke celah sinaptik tadi akan
berikatan dengan AchR yang terdapat di
membran post sinaps.
Asetilkolin diikat oleh 5 sub-unit protein
dari Ach-R dimana akan membentuk sebuah
lingkaran. Ikatan AchR dengan Ach
(Asetilkolin) akan menyebabkan influks
Na+ dimana Na+ ini akan mengakibatkan
terjadinya depolarisasi di post sinaps.
Kontraksi yang terjadi yaitu akibat dari
potensial aksi pada sel otot tersebut. Enzym
juga berperan untuk menghidrolisis Ach
yang masih tertempel pada AchR. Sehingga
untuk mencegah terjadinya kontraksi yang
terus menerus yaitu dengan Asetilkolin yang
akan dipecah menjadi 2 yaitu Kolin dan
Asam Laktat, dimana Kolin akan masuk
kembali kedalam membran pre sinaps dan
membentuk Asetillkolin kembali.
Patofisiologi
Asetilkolin yang dilepaskan dalam jumlah
yang normal, tidak akan memberikan efek
potensial aksi dimana efek potensial aksi
tersebut tidak akan sampai ke membran post
sinaps yang mana pada kondisi Miastenia
gravis ini terjadi penurunan jumlah Ach-R.
Sehingga ketika kekurangan reseptor
tersebut, akan mengakibatkan penurunan
jumlah yang akan diaktifkan oleh saraf dan
otot tertentu. Hal hal ini lah yang
menyebabkan pasien merasa sakit, yaitu
karena kekurangan reseptor dan keberadaan
Ach dalam jumlah normal. Antibodi pada
reseptor asetilkolin itu adalah penyebab
utama kelemahan otot pada penyakit
Miestenia gravis. Pada beberapa orang
mungkin memiliki Miestenia gravis yang
tidak disebabkan oleh antibodi yang
menghalangi asetilkolin, maka dari itu
kondisi yang seperti ini yaitu dimana tidak
disebabkan oleh antibodi yang menghalangi
asetilkolin yaitu disebut sebagai antibodi-
negatif Miestenia gravis. Pada kelenjar
timus juga memiliki peran untuk mendeteksi
adanya Miestenia gravis, yaitu dengan
membesarnya timus dimana hal tersebut
tidak normal.
Epidemologi Kondisi tersebut dapat disertai kelumpuhan
anggota badan terutama triceps dan
Pada penyakit Miastenia gravis ini terjadi
ekstensor jari-jari. kelemahan/kelumpuhan
pada usia muda yang mana sekitar 30tahun
otot lainnya dapat terjadi pada otot
untuk wanita dan 60 tahun untuk pria.
pernafasan sehingga dapat menyebabkan
Miastenia gravis ini juga terjadi dari 20
sesak nafas.
dalam 100.000 populasi yang mana sangat
jarang terjadi. Insiden puncak di umur yang 2. Tes klinik sederhana
lebih awal pada wanita dibandingkan dengan
a). Tes watenberg/simpson test : Pasien
laki laki yaitu karena wanita memiliki
akan diminta untuk melihat objek yang
gangguan imun yang lebih banyak
diletakkan diantara kedua mata pasien.
dibandingkan pria. Sehingga, Miastenia
Apabila dalam kurun waktu > 30 detik mata
gravis memiliki onset yang lebih sering pada
pasien mengalami ptosis (kelopak mata
wanita dibandingkan dengan laki laki. Di
turun sebelah) maka tes dinyatakan positif.
Asia Timur, 50% dari semua kasus memiliki
onset sebelum usia 15tahun pada b). Tes pita suara : Pada tes ini, biasanya
subkelompok mata. Dimana antibodi LRP4 pasien akan diminta untuk menghitung 1-
atau lipoprotein yang terkait dengan protein 100. Apabila suara pasien semakin lama
ini terdapat di pasien tanpa antibodi Ach-R. semakin menghilang maka tes akan
Data epidemologi bahwasanya LRP4 yang dinyatakan positif .
berkaitan dengan Miastenia gravis ini terkait
dengan musk. Tetapi hal ini lebih sering 3. Uji Tensilon (edrophonium chloride)
terjadi pada orang orang yang ada di Eropa. uji tensilon dilakukan dengan menyuntikkan
Faktor yang menyebabkan yaitu bisa dari 2 mg tensilon secara intravena selama 15
luar seperti diet atau infeksi. detik, apabila dalam 30 detik tidak terdapat
reaksi maka volume penyuntikan dinaikkan
sebanyak 8-9 mg tensilon. Setelah tensilon
DIAGNOSIS MIASTENIA GRAVIS disuntikkan, perhatikan otot-otot yang
mengalami pelemahan, biasanya terjadi
Diagnosis untuk penyakit miastenia
pada kelopak mata yang memperlihatkan
gravis diperlukan pengujian yang bersifat
adanya ptosis. Apabila kelemahan otot mata
akurat. Diagnosis penyakit ini dapat
disebabkan oleh Miastenia gravis, maka
ditegakkan berdasarkan beberapa pengujian
ptosis akan pulih. Pada uji ini kelemahan
seperti anamnesis, tes antikolinesterase,
otot mata harus diperhatikan dengan sangat
EMG, serologi untuk antibodi AchR dan
seksama, karena efektivitas dari tensilon
CT-Scan atau MRI toraks untuk melihat
sangat singkat. Efek sampingnya dapat
adanya timoma.
menyebabkan bradikardi dan untuk
1. Anamnesis mengatasinya dapat digunakan atropin.
Anamnesis merupakan kelemahan atau
kelumpuhan otot yang berulang setelah
aktivitas dan membaik setelah istirahat.
Biasanya miastenia gravis menyerang otot
mata dengan manifestasi: diplopi atau ptosis.

4. Uji Prostigmin (neostigmin)
Pada uji prostigmin dilakukan
penyuntikkan 3 cc atau 1,5 mg prostigmin
metilsulfat secara intramuscular
(ditambahkan atropin 0,8 mg apabila
diperlukan). Jika kelemahan otot
disebabkan oleh Miastenia gravis maka
gejala seperti ptosis, strabismus atau
kelemahan lain tidak lama kemudian akan
membaik. Pada pasien tanpa timoma anti-
muscle-specific antibodi dapat menunjukkan
hasil positif pada pasien dengan usia lebih
dari 40 tahun.
Pada Anti-musclespecific kinase
(MuSK), hampir 50% antibodi penderita
Miastenia gravis yang menunjukkan hasil
anti-AChR Ab negatif (Miastenia gravis
seronegatif) dan hasil positif ditunjukkan
dari anti-MuSK Ab. Kemudian Anti-
asetilkolin reseptor antibodi, hasil dari
pemeriksaan dapat digunakan untuk
mendiagnosis suatu Miastenia gravis,
dimana hasil yang postif ditunjukkan pada
70% - 95% dari penderita Miastenia gravis
generalisata dan 50% - 75 % dari penderita
dengan Miastenia okular murni
menunjukkan hasil tes anti-asetilkolin
reseptor antibodi positif. Pada pasien
timoma tanpa mengidap Miastenia gravis
sering kali terjadi false positive anti-AChR
antibody.
6. Elektrodiagnostik
Pemeriksaan elektrodiagnostik dapat
memperlihatkan adanya kerusakan pada
transmisi neuromuskular melalui 2 teknik
yaitu Single-fiber Electromyography
(SFEMG) dan Repetitive Nerve Stimulation
(RNS). Pada pengujian SFEMG mendeteksi
adanya kerusakan transmisi pada
neuromuskular fiber berupa adanya
peningkatan titer dan fiber pada densitas
normal. Pengujian teknik ini menggunakan
jarum single-fiber yang memiliki permukaan
kecil untuk merekam serat otot penderita,
sehingga SFEMG dapat mendeteksi suatu
titer (variabilitas pada interval interpotensial
diantara 2 atau lebih serat otot tunggal pada
unit yang sama) dan fiber density (jumlah
potensial aksi dari serat otot tunggal yang
dapat direkam oleh jarum perekam).
Repetitive Nerve Stimulation (RNS)
mendeteksi adanya penurunan jumlah
reseptor asetilkolin pada penderita Miastenia
gravis, sehingga pada RNS terdapat
penurunan potensial aksi.
7. Gambaran Radiologi
Chest x-ray (foto roentgen thorak)
dapat dilakukan dalam posisi anteroposterior
dan lateral. Pada roentgen thorak, thymoma
dapat diidentifikasi sebagai suatu massa
pada bagian anterior mediastinum. Pada
hasil roentgen negative, belum dipastikan
dapat menyingkirkan adanya thymoma
berukuran kecil. Sehingga perlu dilakukan
chest Ct-scan untuk mengidentifikasi
thymoma pada seluruh kasus Miastenia
gravis, terutama pada penderita dengan usia
tua. Pemerikasaan MRI pada otak dan orbita
sebaiknya tidak digunakan sebagai
pemeriksaan rutin. Namun, MRI dapat
digunakan apabila diagnosis Miastenia
gravis tidak dapat ditegakkan dengan
pemeriksaan lainnya serta mencari
penyebab defisit pada saraf otak.
Autoimun adalah kondisi ketika system
kekebalan tubuh mengalami kelainan
sehingga menyerang jaringan dan saraf yang
sehat pada tubuh. Penyakit myasthenia
gravis ini memiliki banyak gejala. Berikut
gejala pada myasthenia gravis.
Ada beberapa gejala yang terjadi pada
penyakit myasthenia gravis diantarannya:
1. Gejala yg utama yaitu melemahnya
otot otot kerangka misalnya otot
wajah, mata, tenggorokan dan kaki.
Gejala ini terjadi setelah beraktivitas
dan hilang setelah istirahat. Biasanya
otot melemah itu terjadi ketika otot kita
tidak berkontraksi secara normal.
Contoh saja pada otot kaki. Biasanya
kita sulit untuk bergerak ketika kita
duduk kemudian berdiri, pincang dan
kesulitan mengangkat barang.
2. Ptosis (kelopak mata droopy)
Kondisi ini biasanya disebabkan
karena trauma, usia, dan gangguan
kesehatan. Biasannya gejala ini ditandai
turunya kelopak mata bagian atas
sehingga matanya tidak bisa membuka
sepenuhnya atau sempurna, dan
biasanya sipit sebelah. Selain itu pada
ptosis dapat terjadi pada kedua mata
atau bilateral. Kondisi ini menjadikan
mata berair sehingga dapat menganggu
penglihatan kita.
3. Diplopia (penglihatan kabur atau
ganda)
Gejala ini biasanya kita melihat
sesuatu itu tidak persis dengan arah yang
sama atau bersamaan. Jadi kita bisa melihat
sesuatu yang ada bayangannya. Gejala ini
ditandai dengan kelelahan dan banyaknya
mengkonsumsi alkohol.
Diplopia secara umum dibagi menjadi 2
yaitu:
 Diplopia bonikular :
biasanya penderita melihat objek
dengan kedua mata dan kemudian objek
tersebut tidak ada atau hilang ketika salah
satu mata ditutup. Biasanya pada diplopia
bonikular ini ditandai dengan pergerakan
otot bola mata terganggu sehingga sudut
mata nya tidak sinkron.
 Diplopia monocular :
Gejala ini jika salah satu mata
ditutup, maka akan terjadi buram sebelah.
Biasanya terjadi pada penderita katarak,
kornea , lensa mata dan gangguan pada
retina.
4. Kesulitan mengunyah dan menelan
makanan
Gejala ini ditandai adanya nyeri pada
peradangan mulut sehingga menyebabkan
kesulitan untuk mengunyah dan menelan
makanan.
5. Kesulitan berbicara
Gejala ini ditandai ketika berbicara
tidak seperti biasanya. Suara rendah atau
kecil seperti hidungnya tersumbat atau
pengap. sehingga cara berbicaranya itu
tidak bisa lancar.
6. Kesulitan bernafas
Gejala ini ditandai pada Kelemahan
otot pernafasan yang menyebabkan
penderita sulit untuk bernafas. Dada terasa
berat untuk bernafas bahkan bisa terjadi
sesak nafas atau karena melemahnya otot
otot dinding dada.
7. Kehilangan ekspresi wajah
Gejala ini ditandai dengan otot wajah
melemah sehingga kelihatan sulit untuk
menunjukkan ekspresi wajah misalnya
tersenyum.
 Myasthenia gravis juga ditandai
dengan cepat kelelahan setelah
menggerakkan otot. Biasanya penderita
penyakit myasthenia ini memiliki tanda dan
gejala yang berbeda beda. Jika gejala yang
terjadi pada tubuh kita tidak langsung
ditangani, maka gejala tersebut bisa
berkembang semakin parah. Biasanya,
gejala pada myasthenia gravis semakin
memburuk jika kita melakukan banyaknya
aktivitas.
Kondisi melemahnya otot akibat
penyakit myasthenia gravis juga dapat
menyerang bagian tubuh yang lain, seperti
otot leher, lengan dan tungkai. Biasanya
gejala yang sering muncul yaitu :
 Nyeri otot setelah beraktivitas
 Sulit mengangkat kepala setelah
berbaring
 Sulit bergerak, naik turun tangga.
 Dan gangguan dalam berjalan
Dalam kasus myasthenia gravis,
antibody menghalangi , menyerang dan
menghancurkan reseptor asetilkolin yang
dibutuhkasn otot untuk bisa berkontraksi.
Jadi melemahnya otot yang ada pada tubuh
itu menyebabkan otot tidak bisa
berkontraksi. Penyakit myanesthesia gravis
ini sangat berbahaya karena bisa
menyebabkan kerusakan pada otot saraf dan
otot yang lainnya.
Dari gejala yang dialami oleh penderita
penyakit myasthenia gravis biasanya
sembuhnya lama, karena dari gejala tersebut
bisa menyebabkan otot otot dalam tubuh
melemah dan bisa sembuh jika penderita
menghindari atau tidak melakukan banyak
aktivitas dan perlu diwaspadai jika gejala
tersebut semakin parah maka segera
ditangani secepatnya karena gejala yang
terjadi pada penyakit myasthenia gravis
tidak bisa dibuat kerja yang berat atau
beraktivitas terlalu lama.
Algoritme terapi pada myasthenia gravis
Myasthenia gravis merupakan penyakit yang
berkepanjangan (kronis) dan cenderung
memburuk seiring berjalannya waktu.
Penderita myasthenia gravis perlu
melakukan pemeriksaan dokter secara
berkala agar perkembangan penyakit dan
kondisinya dapat terpantau dengan baik.
Penderita myasthenia gravis dianjurkan
untuk segera ke IGD bila mengalami sesak
napas. Kondisi ini dapat berkembang
menjadi henti napas, sehingga penderita
perlu mendapatkan alat bantu pernapasan
secepatnya.Walaupun belum ada cara yang
efektif untuk menyembuhkan myasthenia
gravis, tetapi pengobatan yang diberikan
oleh dokter dapat meredakan gejala,
meningkatkan fungsi otot, dan mencegah
kelumpuhan otot-otot pernapasan yang
berakibat fatal.Jenis penanganannya pun
berbeda-beda untuk tiap penderita,
tergantung usia, tingkat keparahan, dan
kondisi pasien secara keseluruhan.
Beberapa tindakan pengobatan untuk
mengatasi myasthenia gravis adalah:
A. Acetilkolinesterase inhibitor dapat
diberikan piridostigmin bromida
(mestinon) 30-120 mg/3-4 jam/oral.
Dosis parenteral 3-6 mg/4-6 jam/ iv tiap
hari akan membantu pasien untuk
mengunyah, menelan, dan beberapa
aktivitas sehari-hari. Pada malam hari,
dapat diberikan mestinon long-acting 180
mg. Apabila diperlukan, neostigmin
bromida (prostigmine ): 7,5-45 mg/2-6
jam/oral. Dosis parenteral : 0,5-1 mg/4
jam/iv atau im. Neostigmin dapat
menginaktifkan atau menghancurkan
kolinesterase sehingga asetilkolin tidak
segera dihancurkan. Akibatnya aktifitas
 otot dapat dipulihkan mendekati normal,
sedikitnya 80-90% dari kekuatan dan
daya tahan semula. Pemberian
antikolinesterase akan sangat bermanfaat
pada Miastenia gravis golongan IIA dan
IIB. Efek samping pemberian
antikolinesterase disebabkan oleh
stimulasi parasimpatis, termasuk
konstriksi pupil, kolik, diare, salivasi
berkebihan, berkeringat, lakrimasi, dan
sekresi bronkial berlebihan. Efek
samping gastro intestinal (efek samping
muskarinik) berupa kram atau diare dapat
diatasi dengan pemberian propantelin
bromida atau atropin. 2, 8, 10, 12
B. Kortikosteroid
Dapat diberikan prednison dimulai dengan
dosis rawal 10-20 mg, dinaikkan bertahap
(5-10 mg/minggu) 1x sehari selang sehari,
maksimal 120 mg/6 jam/oral, kemudian
diturunkan sampai dosis minimal efektif.
Efek sampingnya dapat berupa: peningkatan
berat badan, hiperglikemia, osteopenia,
ulkus gaster dan duodenum, katarak. 2, 8,
10, 12
C. Azatioprin
Azatioprin merupakan suatu obat
imunosupresif, juga memberikan hasil yang
baik, efek sampingnya sedikit jika
dibandingkan dengan steroid dan terutama
berupa gangguan saluran cerna,peningkatan
enzim hati, dan leukopenia. Obat ini
diberikan dengan dosis 2-3 mg/kg
BB/hari/oral selama 8 minggu pertama.
Setiap minggu harus dilakukan pemeriksaan
darah
lengkap dan fungsi hati. Sesudah itu
pemeriksaan laboratorium dikerjakan setiap
bulan sekali. Pemberian prednisolon
bersama-sama dengan azatioprin sangat
dianjurkan. 2, 12
D. Plasma Exchange (PE)
PE paling efektif digunakan pada situasi
dimana terapi jangka pendek yang
menguntungkan menjadi prioritas.Dasar
terapi dengan PE adalah pemindahan anti-
asetilkolin secara efektif.Respon dari terapi
ini adalah menurunnya titer antibodi.
Dimana pasien yang mendapat tindakan
berupa hospitalisasi dan intubasi dalam
waktu yang lama serta trakeostomi, dapat
diminimalisasikan karena efek dramatis dari
PE.Terapi ini digunakan pada pasien yang
akan memasuki atau sedang mengalami
masa krisis. PE dapat memaksimalkan
tenaga pasien yang akan menjalani
timektomi atau pasien yang kesulitan
menjalani periode pasca operasi. Jumlah dan
volume dari penggantian yang dibutuhkan
kadang-kadang berbeda tetapi umumnya 3-4
liter sebanyak 5x dalam 2 minggu. 4, 10, 12
E. Intravenous Immunoglobulin (IVIG)
Dosis standar IVIG adalah 400 mg/kgbb/hari
pada 5 hari pertama, dilanjutkan 1
gram/kgbb/hari selama 2 hari. 2, 10, 12
F. Timektomi
Timektomi umumnya dianjurkan pada
pasien umur 10-55 tahun dengan Miastenia
gravis generalisata. Walaupun timektomi
merupakan terapi standar di berbagai pusat
pengobatan namun keeefektivitasannya
belum dapat dipastikan oleh penelitian
prospektif yang terkontrol. Timektomi
diindikasi pada terapi awal pasien dengan
keterlibatan ekstremitas bawah dan bulbar
Jika berat firsline dipakai terapi golongan
acetylcholinesterase yaitu piridostigmin atau
mestinon ,jika terapi berhasil maka
dilanjutkan jika tidak diganti dengan
prednisone atau azathioprine jika berhasil
dilanjutkan dengan dosis rendah,jika tidak
berhasil diganti sesuai dengan kondisi
sebagai berikut :
Jika kondisi ringan sampai sedang memakai
terapi berupa micofenolat jika berat
memakai rituximab jika berhasil dilanjutkan
tetapi jika tidak berhasil diganti dengan
imunosupresan lain seperti;
tacrolimus,methotrexate,azathioprine

Referensi
Conti-Fine BM, Milani,Monica
,Kaminski,Henry J. . Myasthenia gravis:
past, present, and future. The Journal of
Clinical Investigation 2006;116(Number 11)
Council for Medical Schemes. 2014. CM s
cript. CM S Cript. (4)
Gilhus, N. E. dan J. J. Verschuuren. 2015.
Myasthenia gravis: subgroup
classification and therapeutic strategies.
The Lancet Neurology. 14(10):1023–
1036.
Havlícek, F. 1981. Myasthenia gravis.
Casopis Lekaru Ceskych.
120(36):1073–1077.
Ropper AH, Brown, Robert H. ,. Adam And
Victor's Principles of Neurology. In:
Myasthenia Gravis And Related Disorders
Of The Neuromuscular Junction 8 th ed.
United State of America: McGraw-Hill
Medical Publishing Division; 2005.
Setiyohadi B. Miologi. In: Sudoyo AW,
Setiyohadi, Bambang, Alwi, idrus,
Simadibrata K.,Marcellus, Setiati, Siti,
editor. Buku Ajar Ilmu Penyakit Dalam.
Jakarta: InternaPublishing; 2009.
Lampiran Jurnal Referensi

Myasthenia gravis: subgroup classification and

therapeutic strategies
Nils Erik Gilhus, Jan J Verschuuren

Myasthenia gravis is an autoimmune disease that is characterised by muscle weakness and Lancet Neurol 2015; 14:
fatigue, is B-cell mediated, and is associated with antibodies directed against the 1023–36
acetylcholine receptor, muscle-specific kinase (MUSK), lipoprotein-related protein 4 (LRP4),
Department of Clinical
or agrin in the postsynaptic membrane at the neuromuscular junction. Patients with Medicine, University of
myasthenia gravis should be classified into subgroups to help with therapeutic decisions Bergen,
and prognosis. Subgroups based on serum antibodies and clinical features include early- Bergen, Norway
onset, late-onset, thymoma, MUSK, LRP4, antibody-negative, and ocular forms of myasthenia (Prof N E Gilhus MD);
Department of Neurology,
gravis. Agrin-associated myasthenia gravis might emerge as a new entity. The prognosis is Haukeland University
good with optimum symptomatic, immunosuppressive, and supportive treatment. Hospital,
Pyridostigmine is the preferred symptomatic treatment, and for patients who do not Bergen, Norway
adequately respond to symptomatic therapy, corticosteroids, azathioprine, and thymectomy (Prof N E Gilhus); and
Department of
are first-line immunosuppressive treatments. Additional immunomodulatory drugs are Neurology, Leiden
emerging, but therapeutic decisions are hampered by the scarcity of controlled studies. University Medical
Long-term drug treatment is essential for most patients and must be tailored to the particular Center, Leiden,
form of myasthenia gravis. Netherlands (Prof J J
Verschuuren MD)
Correspondence to:
Prof Nils Erik Gilhus,
Department

Introduction clinical features can vary. Patients with instrumental for

Dysfunction at the neuromuscular junction
underlies several disorders that are
characterised by skeletal muscle weakness
usually involving some but not all muscle
groups. Genetic forms of these disorders are
termed congenital myasthenic syndromes.
Some toxins, like botulinum toxin and curare,
can cause neuromuscular dysfunction;
acquired antibody-mediated forms include
autoimmune and neonatal myasthenia gravis,
Lambert– Eaton myasthenic syndrome, and
neuromyotonia.
Myasthenia gravis forms the largest disease
group of neuromuscular junction disorders and
is caused by pathogenic autoantibodies to
components of the postsynaptic muscle
endplate (figure 1).1–4 Fluctuations in severity of
muscle weakness are typical. Some, but not all,
muscles are affected and not necessarily
symmetrically. Increased weakness with
continued muscle activity represents a
diagnostic clue for myasthenia gravis, but these
myasthenia gravis should be classified into subgrouping
subgroups, with implications for diagnosis, patients with
optimum therapy, and prognosis. In myasthenia
myasthenia gravis guidelines and consensus gravis. A
reports, subgrouping is recommended,1–5 but
exact definitions vary and new subgroups are
emerging as a result of increased knowledge.
As this subgrouping takes into account
myasthenia gravis autoantibodies,
epidemiology, clinical presentation, and
comorbidities, the subgroups are discussed
after these sections in this Review. For a few
patients, subgrouping is not possible owing to
insufficient precise information, including
suboptimum autoantibody testing and
pathological changes of the thymus below the
detection threshold of imaging.
Autoantibodies against the acetylcholine
receptor (AChR), muscle-specific kinase
(MUSK), and lipoprotein- related protein 4
(LRP4) are well established as sensitive and
specific diagnostic markers and pathogenic
factors, and these autoantibodies are
prerequisite for optimum diagnosis and of Neurology, Haukeland University Hospital, 5021 Bergen,
Norway
treatment, therefore, is access to autoantibody
nils.gilhus@helse-bergen.no
testing.1–5
With modern immunosuppressive,
symptomatic, and supportive treatments, the
prognosis for patients with myasthenia gravis is
good. Most patients with mild-to- moderate
symptoms will obtain full remission or
substantial improvement. Full remission is rare
in severe cases, some variation over time is
common, and steady progression is unusual.
Daily life functions of individuals with
myasthenia gravis are not, or only modestly,
affected and life expectancy is not reduced.6
Long-term drug treatment is necessary for
nearly all patients with myasthenia gravis.2,7 In
10–15% of these patients, full control of the
disease is not possible or is only at the cost of
severe side-effects of immunosuppressive
therapy.8
Treatment protocols at leading centres are
not based purely on results from well
controlled studies or guidelines based on such
studies, because well controlled studies are
sparse for this disease, and do not take into
account the variation in therapeutic response
among the diagnostic subgroups. Myasthenia
gravis is a rare disease, and most patients do
well on existing treatments, both aspects that
are a challenge for new trials. We will combine
information from controlled studies, consensus
reports, and expert views with insights from
theoretical and experimental studies relevant
for myasthenia gravis subgroups, with the aim
of assessing the evidence base for the use of
treatments, including interventions directed at
the patho- physiological process.

Autoantibodies in myasthenia gravis

AChR antibodies are highly specific for
myasthenia gravis, and their presence
combined with muscle weakness confirms the
disease. Further diagnostic investigation is
necessary only to define the subgroup and
disease severity. The value of repeated AChR
antibody testing in patients with this disorder is
debated,
A Standard tests for MUSK antibodies use radio-
Schwann cell
Nerve
ACh Vesicles
Muscle
Agrin Acetylcholin
B C e AChR
LRP4–MUSK
complex
Nerv Nerv
e e
Synaps Synaps
e
e
Muscl Muscl
e e
Figure 1: The neuromuscular junction
(A) The AChR and MUSK are expressed at the top of the junctional folds. (B) Trophic signal: binding of agrin
to the LRP4–MUSK complex activates aggregation of AChRs and promotes transition from the plaque to pretzel
form of the neuromuscular junction. (C) Activation signal: binding of acetylcholine to the AChR induces a
brief opening of the central ion channel causing membrane depolarisation, which in turn elicits a muscle action
potential that leads to contraction of the muscle fibre. AChR=acetylcholine receptor. MUSK=muscle-specific
kinase.
LRP4=lipoprotein-related protein 4.
but changes in antibody concentration might predict
disease severity in patients given immunosuppressive
drugs and therefore can support therapeutic decisions.
No correlation has been shown between AChR antibody
concentration and disease severity. AChR antibodies
are directly pathogenic through crosslinking of AChRs
leading to accelerated degradation of these receptors,
through complement binding and activation, and by
inducing AChR conformational changes or blocking
acetylcholine binding.1–4 Radioimmunoprecipitation is
the standard commercial test and gives a quantitative
AChR antibody measure. Cell-based assays can have an
even higher sensitivity than radioimmunoprecipitation,
but are not yet commercially available and
standardised.9 Tests avoiding radioactive ligands are
also in use such as ELISA and fluorescence tests based
on immuno- precipitation, 10 but they tend to be less
sensitive than assays with radioactive ligands.
immunoprecipitation or an ELISA. Cell-based assays
used for research can increase sensitivity. MUSK
antibodies are directly pathogenic in experimental
animal models,11–13 even if the predominant IgG4
antibodies do not bind complement. Any value of
repeated tests in the follow-up of patients has not been
established because prospective, high-quality studies
have not been done.
LRP4 antibodies bind to the membrane protein in
vivo, block the agrin–LRP4 interaction and thereby also
inhibit AChR clustering in the membrane. Interference
with the LRP4–MUSK interaction might also be a
relevant disease mechanism for this subgroup. Mice
immunised with LRP4 develop typical myasthenia
gravis.14 Thus, LRP4 antibodies are directly pathogenic
through interference with AChR function.
Agrin antibodies have been detected in a few patients
with myasthenia gravis and AChR, MUSK, or LRP4
antibodies.15,16 Agrin is essential for AChR function, but
whether these antibodies contribute to the muscle
weakness in this disease is still unclear. Similarly,
cortactin autoantibodies have been reported in patients
with myasthenia gravis, both with and without other
neuromuscular autoantibodies.17
Titin and ryanodine receptor antibodies occur in
some patients with AChR-associated myasthenia gravis.
Titin maintains the flexibility of the cell structure,
whereas the ryanodine receptor is a sarcoplasmic
reticulum calcium channel that mediates contraction of
the muscle cell. Titin and ryanodine receptor antibodies
probably do not enter the muscle cell in vivo and might
not mediate any muscle weakness, but rather could be
disease markers.18 These antibodies are present with a
high frequency in thymoma- associated myasthenia
gravis, with an intermediate frequency in late-onset
myasthenia gravis, and very rarely in early-onset and
ocular myasthenia gravis; they are not detected by
standard testing in MUSK, LRP4, or antibody- negative
myasthenia gravis.7,19 Titin and ryanodine receptor
antibodies can be used to diagnose a thymoma in
patients younger than 50 years. 19 These antibodies have
been proposed as markers for severe myasthenia gravis
with a need for long-term immunosuppression and no
response to thymectomy. Commercial tests with ELISA
are available for titin but not for ryanodine receptor
antibodies.
Epidemiology
Autoimmune myasthenia gravis has a reported
worldwide prevalence of 40–180 per million people,
and an annual incidence of 4–12 per million people. 20–23
Recently collected figures of prevalence and incidence
tend to be higher than older ones, especially for late-
onset myasthenia gravis, partly explained by increased
case finding and more widespread autoantibody
testing. Population demographics with an increased
number of elderly people and reduced myasthenia
gravis mortality affect incidence and prevalence. AChR-
associated
myasthenia gravis has a bimodal age pattern of
incidence, with a peak in young adults aged about
30 years and then a steady increase in incidence with
increasing age older than 50 years. 20,21 The incidence
peak in young adults is mainly because of the high
frequency in women, typical for many autoimmune
disorders, although late-onset myasthenia gravis is
slightly more frequent in men. No evidence suggests
that the occurrence of this disease is increasing as a
result of a change in external causative factors such as
infections or diet.24
Overall, myasthenia gravis incidence and prevalence
shows little geographical variation; however, this
distribution is not the case for all subgroups of the
disease. Juvenile myasthenia gravis, a subtype of early-
onset disease, has a high frequency in east Asia, in which
up to 50% of all cases have onset before age 15 years,
many of them with ocular symptoms only.22,25 Myasthenia
gravis incidence in children (aged <15 years) in a mixed
population from Canada was 1–2 per million per year,
and highest in those of Asian ethnicity, especially for the
ocular subgroup. LRP4 antibodies were recorded in 19%
of patients without AChR antibodies,5 and MUSK
antibodies in a third of patients without AChR
antibodies.3,4,26 Epidemiological data suggest that LRP4-
associated myasthenia gravis is half as frequent as the
MUSK form of the disease. MUSK-associated myasthenia
gravis incidence is estimated at 0·3 patients per million
per year, with a prevalence of 2·9 per million people, and
is more common in southern than northern Europe.27
Genetic predisposition and external factors linked to
infections or diet are potential explanations for some
geographical variation in this disease and its subtypes.
Clinical presentation
Muscle weakness is a major symptom and sign in
myasthenia gravis. The combination of weakness
localisation, variation in weakness over time, and
exercise- induced weakness usually gives strong clues to
the diagnosis of the disease for all subgroups. In older
individuals with eye muscle weakness and bulbar
symptoms, cerebrovascular disease of the brainstem is
sometimes suspected. In younger individuals, unspecific
fatigue disorders can be part of the differential
diagnoses.1,3,7 Weakness in myasthenia gravis arises in the
extraocular, bulbar, limb, and axial muscles (figure 2).
60% of patients present with ptosis or diplopia, or
both, and in 20% of patients, the disease is restricted
to ocular myasthenia gravis.1–4 Weakness of external eye
muscles is nearly always asymmetrical (figure 3),
whereas limb weakness is symmetrical and more
proximal than distal (figure 2).28 The variability in
symptoms in skeletal muscles is surprising because
they all express the autoimmune target protein. This
variation results from many subtle factors affecting
neuromuscular transmission, muscle cell depolarisation
or contraction, resistance to an immunological attack,
and regenerative capacity of
muscle structures.2,17
SubtypeAChRMUSKLRP4 myasthenia gravis myasthenia gravis Seronegative LEMS
myasthenia gravis myasthenia
gravis
Relative prevalence 80% 4% 2% 5% 4%
Figure 2: Distribution of weakness and relative prevalence of subtypes of myasthenia
gravis AChR=acetylcholine receptor. MUSK=muscle-specific kinase. LRP4=lipoprotein-related
protein 4. LEMS=Lambert–Eaton myasthenic syndrome.
Comorbidities
Patients with early-onset and ocular subgroups of
myasthenia gravis have increased frequency of organ-
specific and general autoimmune disorders, especially
thyroiditis.29 Patients with thymoma-associated
myasthenia gravis are at an increased risk of
developing haematological autoimmune disorders.
Thymectomies have not been shown to increase the
risk of infections, autoimmune disease, or cancer.
Myasthenia gravis muscle weakness might increase the
risk of respiratory infections and osteoporosis,
becoming overweight, and developing other
complications. A widespread autoimmune
inflammatory myopathy can occur in myasthenia
gravis.30 AChR antibodies and myasthenia gravis-like
features have been described occasionally in patients
with amyotrophic lateral sclerosis.31
Several studies32–34 have investigated the cancer risk in
patients with myasthenia gravis and its subgroups.
Methodological challenges due to myasthenia gravis
patient selection, sensitivity in cancer detection, follow-up
time, and types of control groups have led to varying
conclusions. Thymomas in general seem to confer a
moderately increased risk for other cancer types, 32
whereas myasthenia gravis and its immunoactive
treatment, according to a Danish population-based study 33
with a long-term follow-up and relevant controls, was
not associated with a significantly increased risk,
perhaps with the exception of non-melanoma skin
cancer.34
AChR, MUSK, and LRP4 antibodies do not cross-react
with the heart muscle. In population studies,6 no
increased mortality or morbidity related to cardiac
factors have been established. However, cardio-
physiological function can be marginally affected by
these antibodies.35 Many case reports of severe
cardiomyositis and heart conduction abnormalities in
thymoma-associated myasthenia gravis and late-onset
myasthenia gravis have been noted, most probably
induced by heart muscle autoimmunity. 36,37 Heart
function monitoring is recommended during severe
myasthenia gravis exacerbations, especially in patients
with various antimuscle antibodies.38
 A B C

Figure 3: Two patients with AChR-associated myasthenia gravis

Female patient with ophthalmoplegia (note adduction of right eye) and ptosis of the left eye (A). Male patient with opthalmoplegia (note the upward position of the
left eye) and ptosis of the right eye before treatment (B) and 1 year after immunosuppressive treatment (C).

Myasthenia gravis subgroups detectable AChR antibodies and

Early-onset myasthenia gravis with AChR antibodies generalised disease. About 30% of
Patients with early-onset myasthenia gravis have, by patients with a
definition, onset of their first symptom before age

50 years (table 1).1,7,39 Serum AChR antibodies are

detected by standard diagnostic testing. Patients with a
thymoma detected on imaging or during surgery are
excluded from this myasthenia gravis subgroup.
Thymic follicular hyperplasia occurs often but is not a
prerequisite, and this group responds to thymectomy.
Female cases outnumber male cases by three to one. 20,22
Early-onset myasthenia gravis has an association with
HLA-DR3, HLA-B8, and other autoimmune risk genes
(table 1),40,41 and all autoimmune disorders are more
widely reported in relatives of patients in this
myasthenia gravis subgroup.42 These findings suggest
subgroup differences in the pathogenesis of myasthenia
gravis.

Late-onset myasthenia gravis with AChR antibodies

Patients with late-onset myasthenia gravis are defined
as having their first onset of symptoms after age 50
years. In this group, serum AChR antibodies are
present, thymoma is not evident on imaging or during
surgery, and thymic hyperplasia occurs only rarely;
these patients most often will not respond to
thymectomy. The disease is slightly more frequently
reported in males than females, and weak HLA
associations occur with HLA- DR2, HLA-B7, and HLA-
DRB1*15:01.43

Thymoma-associated myasthenia gravis

Thymoma-associated myasthenia gravis is a para-
neoplastic disease. Myasthenia gravis is by far the most
widely reported autoimmune disease associated with a
thymoma, although pure red aplasia and
neuromyotonia are also associated with thymoma; this
association does not occur in other autoimmune
disorders. A thymoma is recorded in 10–15% of all
patients with myasthenia gravis. Nearly all have
thymoma develop myasthenia gravis, and even more have AChR
antibodies without myasthenia gravis. 44

MUSK-associated myasthenia gravis

MUSK is a protein expressed in the postsynaptic muscle membrane that is
functionally linked to AChR and necessary to maintain AChR function.
Overall, 1–4% of patients with myasthenia gravis have serum MUSK
antibodies, but more cases will probably be identified with increasingly
sensitive test assays. MUSK and AChR antibodies rarely coexist in the same
patient. MUSK- associated myasthenia gravis is usually reported in adults,
and rarely in the very old or in children. 45 No thymus pathological changes
are reported and patients usually have no response to thymectomy. IgG4
antibodies have an important role in the pathogenesis, and there is an HLA
association with HLA-DQ5,46–48 unlike in other myasthenia gravis
subgroups.
MUSK-associated myasthenia gravis shows pre- dominant involvement
of cranial and bulbar muscles. About a third of the patients present with
ptosis and diplopia.27 In more than 40% of patients with MUSK- associated
myasthenia gravis, bulbar weakness is a first symptom, with facial,
pharyngeal, and tongue weakness, often associated with neck and
respiratory involvement. Limb weakness is not common, and ocular
muscles are often unaffected.27 Little variation in muscle strength is
reported during the day, and muscle atrophy might occur.

LRP4-associated myasthenia gravis

LRP4 is expressed in the postsynaptic muscle membrane; it is a receptor
for nerve-derived agrin and an activator of MUSK, and is necessary to
maintain AChR function. LRP4 antibodies have been detected in 2–27% of
patients with myasthenia gravis without AChR and MUSK antibodies, with
a female pre- ponderance.49,50 Most of these patients present with ocular or
generalised mild myasthenia gravis, and about 20% of patients have
only ocular weakness for
more than 2 years. Respiratory insufficiency occurs
Myasthenia Age at onsetSex gravis HLA Thymus
very rarely, except in a subgroup with additional MUSK subgroup associations pathological
antibodies. In two-thirds of patients with LRP4- changes
Active immune response
associated myasthenia gravis, the thymus is atrophic
and normal for age, but hyperplasia has been reported. 5 AChREarly onset<50 years More female than male DR3-B8-A1Hyperplasia
Commercial tests are not yet available for LRP4
antibody testing, meaning that this group can be AChRLate onset>50 years More male than female Diverse Normal or
identified only by a few institutions. hyperplasia
AChR Thymoma Variabl ·· ·· Lymphoepitheliom
Antibody-negative generalised myasthenia gravis MUSK MUSK- e Substantially DR14, a Normal
Myasthenia gravis without detectable AChR, MUSK, or myastheni Variabl more female than DR16, DQ5
a gravis e male
LRP4 antibodies represents a heterogeneous group
LRP4 LRP4- Variabl ·· ·· Normal
pathogenically. Some patients have low-affinity anti- myastheni e
bodies or low concentration of antibodies to AChR, a gravis
MUSK, or LRP4 antigen targets, identified by cell-based Unknown SNMG Variabl ·· ·· Normal or
methods only, that are not detectable in routine e hyperplasi
assays.51,52 Low-affinity antibodies are pathogenic in Passive transfer of a
vivo, and the disease in patients with such antibodies is antibodies
AChR, or NeonatalNeonate Equal proportion ·· None
probably similar to that in the myasthenia gravis MUSK, or myasthenia of female to male
LEMSgravis
subgroup with detectable antibodies. Low-affinity
antibodies seem to account for 20–50% of patients in AChR=acetylcholine receptor. MUSK=muscle-specific kinase. LRP4=lipoprotein-related
the antibody-negative generalised myasthenia gravis protein 4.
SNMG=seronegative myasthenia gravis. LEMS=Lambert-Eaton myasthenic syndrome.
subgroup.51,52 Antibodies to agrin and cortactin often
occur in combination with other autoantibodies. 15,17,52 Table 1: Myasthenia gravis antibody and subgroup characteristics
Their functional relationship to other targeted proteins
is not clear. Some patients with myasthenia gravis elements of the thymus and are active in early-onset
probably have pathogenic antibodies against yet- myasthenia gravis, whereas thymoma cells contain
undefined antigens in the postsynaptic membrane. The muscle-specific antigens and have antigen-presenting
diagnosis is more challenging in patients in whom no properties.54 AChR expression can be activated in
specific autoantibodies are detected. In such patients, thymic epithelial cells through cytokine and receptor
non-myasthenia gravis myasthenic syndromes and signalling, potentially triggered by a virus; 3,55 however,
other muscle and non-muscle disorders should also be no specific virus has been identified so far. MicroRNAs
considered.3 can mediate immunoregulatory processes, be induced
by environ- mental events, and seem to be abnormally
Ocular myasthenia gravis expressed in myasthenia gravis.56 Autoreactive T cells,
In some patients with myasthenia gravis, the weakness specific for AChR, escape the normal intrathymic
is restricted to the ocular muscles. Patients with purely surveillance and are exported to the periphery where
ocular weakness are at risk of developing generalised they stimulate B cells to produce antibodies.
myasthenia gravis, especially early in the disease. 90% Differences in autoantibody pattern, HLA associations,
of those who have had the ocular form for more than 2 thymic pathological changes, cytokine intrathymic
years will remain in this subgroup. 53 Half of patients pattern, and T-cell subsets and clones all point to
with ocular myasthenia gravis have detectable AChR differences in induction mechanisms for early-onset,
antibodies, whereas MUSK antibodies very rarely late-onset, and thymoma-associated myasthenia
occur.53 gravis.44

Thymus pathological changes Neurophysiological testing

Thymoma, but no other thymic tumours, is associated
with myasthenia gravis. Thymic hyperplasia is reported
in most patients with early-onset myasthenia gravis
and in some patients with late-onset, ocular, and
antibody- negative disease. CT scanning or MRI of the
mediastinum should be undertaken in all patients with
myasthenia gravis to assess for a thymoma. 1–4,7 Both
sensitivity and specificity are challenges for imaging.
Experimental and clinical evidence strongly suggests
that early-onset and thymoma-associated myasthenia
gravis are initiated within the thymus.44 Myoid muscle-
like cells and professional antigen-presenting cells are
Neurophysiological tests are unnecessary in patients
with typical myasthenia gravis symptoms because
diagnosis can be confirmed by specific antibody tests;
these tests are also not helpful for myasthenia gravis
subgroup classification. However, they are important
for correct diagnosis in patients with myasthenia gravis
without detectable autoantibodies.
Repetitive nerve stimulation and single-fibre electro-
myography for an increased jitter are useful tests for
patients with myasthenia gravis. Single-fibre testing is
the most sensitive, whereas decrement at repetitive
stimulation is the most specific.1 Both sensitivity and
 specificity rely on investigation quality. Even after patients for whom some doubt about diagnosis remains
combined neurophysiological and antibody testing, after testing, from our experience, do not have auto-
myasthenia gravis can be difficult to rule out. Most immune myasthenia gravis.

Drug Control or comparator Number of Duration Primary outcome ClinicalTrials. Result

participants measure gov number
Corticosteroids
Mount (1964)58 Corticotropin Placebo 43 12 weeks Eye movements ·· No significant difference
Howard et al (1976) 59 Alternate-day prednisone Placebo 13 24 weeks Clinical score ·· No significant difference
Lindberg et al (1998) 60 Pulse methylprednisone Placebo 19 2 weeks Muscle fatigue test ·· p<0·01
Benatar et al (2015)61 Prednisolone Placebo 11 16 weeks Treatment failure NCT00995722 Completed
Assistance Publique— Slow decrease of Rapid decrease 118 60 weeks Minimal NCT00987116 Ongoing
Hôpitaux de Paris prednisolone plus of prednisolone manifestation
(2009–2015) azathioprine plus
azathioprine
Azathioprine
Bromberg et al (1997) 62 Azathioprine Prednisone 10 52 weeks Observational ·· Descriptive
Palace et al (1998)63 Prednisolone and Prednisolone and placebo 34 156 weeks Prednisone dose ·· p=0·02
azathioprine
Ciclosporin
Tindall et al (1987)64 Ciclosporin Placebo 20 52 weeks QMGS, AChR titre ·· Only QMGS significant
Tindal et al (1993)65 Ciclosporin Placebo 39 26 weeks QMGS, AChR titre ·· p=0·004
Tacrolimus (FK506)
Nagane et al (2005)66 FK506 Placebo 34 52 weeks Prednisone dose ·· p<0·05
Yoshikawa et al (2011) 67 Tacrolimus Placebo 80 28 weeks Prednisone dose NCT00309088 No significant difference
Astellas Pharma Inc (2011– Tacrolimus Placebo 83 24 weeks QMGS NCT01325571 Ongoing
14)
Mycophenolate
Meriggioli et al (2003) 68 Mycophenolate mofetil Placebo 14 20 weeks QMGS ·· No significant difference,
except SFEMG (p=0.03)
Hoffmann-La Roche Mycophenolate mofetil Placebo 136 36 weeks Responder status NCT00683969 Completed
(2004–07)
Hoffmann-La Roche Mycophenolate mofetil Placebo 136 12–52 weeks Adverse events NCT00408213 Completed
(2004–07)
FDA Office of Orphan Mycophenolate mofetil Placebo 80 12 weeks QMGS NCT00285350 No significant difference
Products
Development/Duke
University, NC, USA (2008)
Sanders et al (2008)69 Mycophenolate mofetil Placebo 176 36 weeks Myasthenia gravis ·· No significant difference
composite
Qualitix Clinical Research Co Mycophenolate mofetil Azathioprine 40 52 weeks Remission NCT00997412 Completed
Ltd (2009–11)
Methotrexate
Pasnoor et al (2013) 70 Methotrexate Placebo 50 36 weeks Prednisone dose NCT00814138 Ongoing
Immunoglobulin or plasma exchange
Gajdos et al (1997) 71 Plasma exchange vs ·· 87 15 days Myasthenic muscular ·· No significant difference
intravenous score
immunoglobulin
Wolfe et al (2002) 72 Intravenous Placebo 15 6 weeks QMGS ·· No significant difference
immunoglobulin
Gajdos et al (2005) 73 Intravenous Placebo 173 2 weeks Myasthenic muscular ·· No significant difference
immunoglobulin score
(two doses)
Zinman et al (2007) 74 Intravenous Placebo 50 4 weeks QMGS NCT00306033 Intravenous
immunoglobulin immunoglobulin effective
(p<0.047)
Barth et al (2011)75 Intravenous Plasma exchange 84 2 weeks QMGS NCT01179893 Equally effective
immunoglobulin
Benesis Corporation Intravenous Plasma exchange 46 4 weeks QMGS NCT00515450 Completed
(2007–10) immunoglobulin
(GB-0998)
(Table 2 continues on next page)
 Drug Control or comparator Number of Duration Primary outcome ClinicalTrials. Result
participants measure gov number
(Conintued from previous page)
Rituximab
Yale University, CT, USA Rituximab Placebo 50 52 weeks Prednisone dose NCT02110706 Ongoing
(2014–17) reduction
Eculizumab
Howard et al (2013)76 Eculizumab Placebo 14 18 weeks QMGS, adverse NCT00727194 p=0·0144
events
Alexion Pharmaceuticals Eculizumab Placebo 92 26 weeks Myasthenia gravis NCT01997229 Ongoing
(2013–16) ADL score
Belimumab
GlaxoSmithKline (2013–14) Belimumab Placebo 42 24 weeks QMGS NCT01480596 Ongoing
Leflunomide
First Affiliated Hospital, Sun Leflunomide Azathioprine 158 48 weeks Clinical response NCT01727193 Ongoing
Yat-Sen University, China
(2012–15)
Tirasemtiv (CK-2017357)
Sanders et al (2015) 77 CK-2017357 Placebo 32 2 days QMGS, VC, MMT NCT01268280 Completed

Thymectomy
University of Alabama at Thymectomy plus Prednisolone 150 3 years AU QMGS NCT00294658 Ongoing
Birmingham, AL, USA/ prednisolone
National Institute of
Neurological Disorders and
Stroke, USA (2008)

Treatment of myasthenia gravis effects have not been

Symptomatic drug treatment
Drugs that increase the amount of acetylcholine at
neuromuscular endplates after motor nerve stimulation
improve muscle weakness in all myasthenia gravis
subgroups; pyridostigmine is the preferred drug for
symptomatic treatment.7 Other acetylcholinesterase
inhibitors, such myasthenia
QMGS=quantitative as neostigmine and ambenonium
gravis score. AChR=acetylcholine receptor. SFEMG=Single-fibre electromyography. ADL=activities of daily living. VC=vital capacity. MMT=manual
muscle have
chloride, test. AU=area underdurations
different the curve. of action and can differ
regarding side-effects. The improvement reported in
Table 2: Randomised trials of treatments for autoimmune myasthenia gravis
patients with these drugs is so specific that it is used as a
diagnostic clue in patients who are antibody negative.
Reduction of acetylcholine breakdown by
acetylcholinesterase inhibition is the most effective
symptomatic treatment in myasthenia gravis, and is
better than increasing acetylcholine release
presynaptically, although a mild beneficial effect of
ephedrine or 3, 4-diaminopyridine might be seen. The
observational effects are so clear that randomised studies
have not been undertaken and are difficult to justify.57 In
MUSK-associated myasthenia gravis, acetylcholinesterase
inhibitors are less effective and induce frequent side-
effects.27 The optimum dose is a balance between
increased muscle strength and side-effects due to
cholinergic stimulation in the autonomic nervous system.
Glycopyrronium bromide, atropine sulfate, and
loperamide can be used to treat muscarinergic side-
effects. Long-term treatment with acetylcholinesterase
inhibitors is safe and habituation or cumulative side-
reported. Some patients with no
or only very mild symptoms
choose to continue to take an
acetylcholinesterase inhibitor.
This continuation might be out
of habit or concern of disease, or
because the inhibitors induce a
substantial subjective
improvement in these patients.

Immunosuppressive drug treatment

For patients with myasthenia
gravis in all subgroups who do
not have a fully satisfactory
functional result with
symptomatic treatment alone,
immunosuppressive drugs
should be initiated (tables 2,3,
and figure 4). Both treatment
effects and side-effects are
dose dependent. Finding the
optimum drug dose for each
patient is as important as
selecting the optimum drug. To
maximise effect and minimise
side-effects, a combination of
immunosuppressive drugs is
preferable for most patients.
Placebo-controlled studies and
those comparing alternative
treatments are rare.
Recommendations are
generally based on the sum of
many studies with weak
evidence, or on guidelines,
clinical experience, and
consensus reports.78 Formal
standards for patient
assessment can be helpful to
assess treatment response.79
Prednisone and prednisolone
improve muscle strength in all
myasthenia gravis subgroups.
Prednisone and prednisolone
are used in the same manner
and are equally effective.
Prednisone is activated by the
liver into prednisolone. The
beneficial effect manifests
after 2–6 weeks, faster than for
most other treatments. In a few
 Number of Duration Study design ClinicalTrials.gov prednisolone should not be given as an alternate-day
Study period
participants number treatment to patients with diabetes because fluctuations
Bortezomib 18 6 months Open NCT02102594 in glucose concentrations result from this treatment
2014–16
GM-CSF 12 120 days Open NCT01555580 approach. If muscle strength differs for off-treatment
2012–13
2013–14 days and on-treatment days, a low dose (5–10 mg) of
Plasmapheresis 10 14 weeks Observational NCT01927692 prednisone or prednisolone can be added on off-days.
For
2004–09
Rituximab 10 12 months Open NCT00619671 ocular myasthenia gravis, observational studies53,82
2008–11
Rituximab 30 12 months Open NCT00774462 suggest that prednisolone treatment reduces the risk of
2002–16
Stem-cell therapy 10 5 years Open, phase 1 NCT00424489 developing generalised myasthenia gravis, although this
2014–17
Subcutaneous 25 12 weeks Open, phase 2 NCT02100969 observation has not been confirmed. For patients who
intravenous
immunoglobulin take long-term corticosteroids, specific precautions
Subcutaneous 10 6 months Open NCT01828294 2011–15 should be taken to reduce the risks of glucose
intravenous
immunoglobulin intolerance, gaining excess bodyweight, hypertension,
development of osteoporosis. A UK registry-based
Tacrolimus 11 28 weeks Open NCT00309101 2006–09 and 83
study did not report an increased fracture risk in
patients with
GM-CSF=granulocyte-macrophage colony stimulating factor.
myasthenia gravis.
Azathioprine is an effective drug for all myasthenia
Table 3: Ongoing non-randomised trials of treatments for autoimmune myasthenia gravis gravis subgroups, with 2–3 mg/kg being the most
registered in ClinicalTrials.gov

maximum effect. Prednisone or

Myasthenia gravis diagnosis confirmed

Start acetylcholine esterase inhibitor and

undertake thymectomy (if early onset or
thymoma)

Yes Continue with acetylcholine

Clinical esterase inhibitor
remission?
No

Start prednisolone and

azathioprine

Continue with prednisolone

Yes (lowest possible dose) and
Very good clinical
azathioprine
effect?
No

Start mycophenolate mofetil (mild,

moderate symptoms) or rituximab (severe
symptoms)

Yes Continue treatment

Sufficient
effect?

No immunosuppressive drugs
A Start other
(methotrexate, ciclosporin, tacrolimus)
B Re-evaluate myasthenia gravis

Figure 4: Treatment of generalised myasthenia gravis

patients, initial deterioration of generalised myasthenia

gravis has been reported lasting for up to 3 weeks.7,54,80
The starting dose is most often 0·75–1·0 mg/kg per
day1 for prednisone and prednisolone and is gradually
increased; alternate-day dosing is thought to reduce
side-effects and is recommended by some treatment
guidelines.2,3,81 After optimum improvement has been
induced, the drug dose should be gradually reduced,
and continued at the lowest dose necessary to obtain
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2015
This combination is often recommended as a first-choice treatment for
patients with generalised myasthenia gravis who need
immunosuppression, and is more beneficial than corticosteroids alone
with fewer side- effects. The azathioprine effect is delayed and from
clinical experience is usually seen after 6–15 months, and might further
increase during the subsequent 1–2 years.63 This makes the combination
with prednisolone convenient, and prednisolone can be reduced when the
azathioprine effect has been established. Regular follow- up is necessary
because of the risk of leucopenia and hepatotoxic effects, especially during
the first months of treatment. Low thiopurine methyltransferase activity
increases the risk for azathioprine toxic effects, and can be tested before
the start of treatment. Long-term treatment is also safe and effective in
young individuals.85 Azathioprine and corticosteroids in combination are
effective in almost all patients with myasthenia gravis. Patients with
ocular myasthenia gravis often respond well to a small dose (10–30 mg on
alternate days) of corticosteroids alone.
Mycophenolate mofetil is a prodrug that after conversion blocks purine
synthesis and interferes with B-cell and T-cell proliferation. Most
guidelines recommend the drug for mild and moderate myasthenia gravis
if the initial immunosuppressive therapy fails, 2–4 often together with
prednisolone. This recommendation is based on retrospective studies 1–3,8
and clinical experience. Mycophenolate mofetil is not recommended as
first-line treatment. In two prospective and controlled trials,69,86
mycophenolate mofetil did not show additional benefit when given as
initial treatment combined with prednisone. The studies had short
durations of only 12 weeks and 9 months. There were no stopping rules
for the use of corticosteroids and the lowest prednisone dose was 7·5 mg
per day, which might have obscured an effect of mycophenolate mofetil.
Little is known about myasthenia gravis subgroup responses for this
drug.87

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2015
 insufficient
Side-effects are rare, with mild headache, nausea, and
diarrhoea the most commonly reported.
Rituximab has emerged as a potentially effective drug
in myasthenia gravis.81,88,89 It is a chimeric IgG1
monoclonal antibody that depletes all types of
B lymphocytes through specific binding to the
transmembrane CD20 antigen. This drug should, in our
opinion, be considered in moderate and especially
severe myasthenia gravis that does not respond
sufficiently to first-line immunosuppressive treatment.
However, controlled studies have not been done, and
rituximab is not regarded as a fully established
treatment. About two- thirds of patients with severe
myasthenia gravis and insufficient response to
prednisolone and azathioprine have a substantial
improvement on this treatment. 81,88–91 Open and
uncontrolled studies90–92 show that patients with MUSK-
associated myasthenia gravis in particular have a
favourable response, which is especially important as
this myasthenia gravis subgroup often has a lower
response to the first-line symptomatic and immuno-
suppressive treatment. In most reports, the induction
treatment recommended for rheumatological diseases
has been used, which is two doses of rituximab 1000
mg, and then another two doses of 1000 mg after 2
weeks.81,88–91 Lower doses have been suggested for
myasthenia gravis.88 Most centres would give additional
rituximab doses only to patients with deterioration
after a substantial and long- lasting response, and then
in the lowest effective dose.92 Rituximab is most often
combined with prednisolone and the combination with
prednisolone and azathioprine is also regarded as safe.
Severe side-effects have been reported as rare events
with rituximab for other autoimmune disorders,
including JC-virus-related pro- gressive multifocal
leukoencephalopathy, and have restricted the use of
rituximab in myasthenia gravis. Even in the absence of
controlled prospective studies and with high drug
costs, rituximab has, in our opinion, a place as an early
treatment for an increasing number of patients with
MUSK and AChR-associated myasthenia gravis.
Prospective and controlled studies have shown that
ciclosporin and methotrexate are effective as secondary
drugs for myasthenia gravis.65,70,93 The effect occurs in all
myasthenia gravis subgroups. Although comparative
studies have not been undertaken, ciclosporin and
methotrexate are thought to be as effective as
azathioprine.1–4,7 Patients should be monitored for
potential side-effects, especially nephrotoxic effects and
hypertension.
Tacrolimus has similarities to ciclosporin. A small
(34 patients) randomised but unblinded study 66 showed
that prednisone could be given at a reduced dose after
52 weeks when combined with tacrolimus. However, a
large double-blind study67 comprising of 80 patients did
not confirm this finding. The length of this study was
only 28 weeks and the therapeutic effect of prednisone
alone was better than expected.94 A new trial comparing
tacrolimus with placebo for patients with an
 convincing data support surgery for this group.
response to glucocorticoids is in However, some guidelines7 recommend treating young
progress (NCT01325571). patients (up to age 60–65 years) with late-onset disease
Tacrolimus has an additional who have an enlarged thymus on imaging and no
effect on ryanodine receptor- antibodies to muscle titin or the ryanodine receptor,
mediated calcium release from similar to patients with early-onset myasthenia gravis.
the sarcoplasmic reticulum, For younger patients with late-onset myasthenia gravis,
which theoretically could lead to the thymus is most probably involved in the
improvements in muscle pathogenesis and the response to thymectomy would
strength in patients with be expected to be similar to that for early-onset disease.
myasthenia gravis. Thymectomy is not recommended for patients with
MUSK, LRP4, or ocular forms of myasthenia gravis as
Thymectomy no therapeutic effect has been shown. For patients with
Many studies have reported a generalised myasthenia gravis and low-affinity AChR
substantial effect of antibodies, thymus hyperplasia is usually impossible to
thymectomy in myasthenia establish by imaging. Such patients would be expected
gravis. These studies have to respond to thymectomy but cannot be distinguished
included control groups, but from other patients with myasthenia gravis who are
prospective and randomised found to be antibody negative.
studies have not been done. 1– Thymectomy should be done early, but is never an
3,7,95,96
For early-onset emergency; patients should be in a stable condition.
myasthenia gravis, we Intravenous immunoglobulin or plasma exchange
recommend a thymectomy immediately before surgery will improve the
early after symptom onset. All myasthenia gravis symptoms, reduce the risk of
thymus tissue needs to be complications, and contribute to a faster recovery.
removed. Video-assisted
thoracoscopic and robotic-
assisted methods are well
established, used by an
increasing number of centres,
and are usually preferred by
patients.97 Thymectomy can be
safe for juvenile myasthenia
gravis, down to an age of about
5 years.98 Improvement in
response to thymectomy occurs
gradually after some months,
and according to follow-up
studies, continues for up to 2
years postoperatively.95 No
other autoimmune disorders
have been shown to improve
after thymectomy.
Thymectomy should be
undertaken as an oncological
intervention when a thymoma
is detected or is strongly
suspected to avoid local
compression and spread to the
thoracic cavity. Any positive
effect on myasthenia gravis is
more unpredictable for the
thymoma than for the early-
onset subgroup.
Use of thymectomy in late-
onset myasthenia gravis is
debated. For patients with late-
onset disease with an atrophic
thymus or onset at age 60–65
years or older, thymectomy is
not recommended because no
 Supportive treatment
Physical activity and low intensity and medium
intensity training provide short-term and long-term
benefits for patients with myasthenia gravis. Weakness
increases with repetitive muscle use, but patients with
myasthenia gravis can still find activities for which they
can adjust intensity and duration to increase their long-
term physical ability. Rest after such exercise is needed.
No controlled studies of myasthenia gravis training
programmes have been published.
Bodyweight control is important, as for other
disorders with muscle weakness. Such control is
especially relevant in patients with involvement of
respiratory muscles. Infections in patients with
myasthenia gravis should be treated early and
vigorously because they can lead to myasthenia gravis
exacerbation and add to respiratory impairment. 1–4,7
Drugs that interfere negatively with neuromuscular
transmission should be avoided. D-penicillamine and
telithromycin should not be given to patients with
myasthenia gravis, and fluoroquinolones,
aminoglycosides, macrolides, and neuromuscular
blocking drugs will often cause worsening of the disease.
Neuromuscular blockade should be used with care during
anaesthesia. Sedatives that could suppress respiration
should be avoided in the treatment of patients with
severe myasthenia gravis. If a patient deteriorates when
given a new drug, this drug should be withdrawn.
However, most patients with myasthenia gravis with
mild-to-moderate disease, or in stable remission, tolerate
drugs that have a relative warning, and most drugs can
be used with caution.
Severe, generalised myasthenia
gravis
Treatment of myasthenia gravis crisis
Crisis is defined as a need for intubation for respiratory
support caused by muscle weakness related to the
disease. Treatment includes intensive care with
respiratory support, treatment of infections, and
monitoring of vital functions and mobilisation (figure
5). Intravenous immunoglobulin and plasma exchange
are specific immunosuppressive treatments with a
rapid effect occurring after 2–5 days, and either one
should be given to patients with severe myasthenia
gravis exacerbations and always for crisis.99–103 These
two treatment alternatives are equally effective, and
can be given in sequence if necessary, as patients can
respond to one but not to the other. Standard protocols
include treatment for 3–6 consecutive days.
Intravenous immunoglobulin is often slightly more
convenient and with a lower risk of severe side-effects,
whereas plasma exchange might have a slightly faster
effect. Catheter placement procedures for plasma
exchange can be complex because access to large veins
is necessary. The treatment effect is usually restricted
to 2–3 months, owing to continuing antibody synthesis.
Plasma exchange and intravenous immunoglobulin can
be repeated when the effect tapers off. To secure long-
term improvement, this treatment is usually combined
with standard immunosuppressive drugs, in higher
doses than before the crisis or with add-on drugs. In
patients with an acute exacerbation that does not
respond to intravenous immunoglobulin or plasma
exchange, corticosteroids in high doses can be tried.
Myasthenia gravis crisis is a reversible condition.
Sometimes the treatment response is delayed, but
intensive care and vigorous immunosuppression should
be continued for as long as necessary, sometimes for
several weeks.

Start intensive care, respirator if

necessary, start intravenous
Treatment of myasthenia gravis in pregnancy
immunoglobulin or plasma exchange Pregnancy does not affect myasthenia gravis in any
consistent way, with no increased risk of severe
Start or continue and intensify deterioration or myasthenia gravis crisis.85,104,105 During
Improvement
Yes long-term immunosuppressive the first weeks and few months post partum, the risk of
treatment
? symptom worsening is moderately increased, mainly
No because of stress and new demands.
Start plasma exchange or
Pyridostigmine and corticosteroids are regarded as
intravenous immunoglobulin safe treatments for pregnant women. 85 These drugs do
Start corticosteroids in high-dose not increase the risk of fetal malformations or delayed
methylprednisolone*
fetal development. Plasma exchange and intravenous
immunoglobulin can be used safely for exacerbations in
Yes
Continue and intensify pregnancy, and also as preparation for women giving
long-term immunosuppressive
Improvement
treatment birth. Evidence for potential teratogenic effects of other
?
immunosuppressive drugs is sparse. However, caution
No
is recommended for use of these drugs, and the
Start rituximab (outside intensive care manufacturers of immunosuppressive drugs generally
unit), continue intensive care and treat
complications advise against their use in pregnancy. Azathioprine has
been widely used for many years by young women with
AChR, MUSK, or LRP4 forms of myasthenia gravis. The
Figure 5: Treatment of severe myasthenia gravis exacerbations
general view is that this drug has very low, if any,
*1000 mg a day for 3 days.
increased teratogenic risk.85 Lactation should be
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encouraged in

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10
 respond sufficiently to standard treatment, with a diagnosis confirmed by the
patients with myasthenia gravis, also for women on presence of
immunosuppressive drugs,105 but the passage of some
medications into breastmilk should be taken into
account. Mycophenolate mofetil and methotrexate have
teratogenic potential. Methotrexate might also reduce
female fertility. These two drugs should only rarely be
used in young women, and not in pregnancy.
Most female patients with myasthenia gravis give
birth in an uncomplicated way. Apart from the risk of
neonatal myasthenia gravis, no precautions are usually
needed. Caesarean section is not recommended as a
routine for these women, but should be considered in
prolonged births for women with moderate or severe
generalised myasthenia gravis because of muscle
fatigue.

Treatment of neonatal myasthenia gravis

Neonatal myasthenia gravis occurs in 10–15% of babies
of mothers with the disease. The cause of this transient
muscular weakness in these babies is transfer of the
mother’s AChR or MUSK antibodies of the IgG class
across the placenta. This weakness usually lasts for only
days or a few weeks and is typically mild but can
interfere with feeding and respiration. Mothers with
myasthenia gravis should always give birth at hospitals
experienced in respiratory support treatment for
newborn babies. The fact that neonatal myasthenia
gravis does not occur in all babies and that occurrence in
babies is not correlated with maternal disease severity
or AChR antibody concentration might be explained by
variation in AChR epitopes, epitope- binding affinity, and
non-AChR factors.105
Transplacental AChR antibodies can, in rare cases,
produce arthrogryposis due to severe intrauterine
movement inhibition. Such skeletal malformations were
reported in three of 127 babies in an unselected national
cohort.106 Arthrogryposis, AChR-antibody induced still-
births, and repeated spontaneous abortions can be
avoided by intravenous immunoglobulin infusions or
plasma exchange before and during pregnancy. This
treatment should be given in female patients with
myasthenia gravis who have already experienced such a
pregnancy outcome.

Conclusions and future directions

Most patients with myasthenia gravis do well and have
well controlled disease. However, most need long-term
and often life-long drug treatment with
acetylcholinesterase inhibitors and usually low-dose
immunosuppression. Pathogenic autoantibodies are
well characterised and myasthenia gravis subgroups
are defined accordingly. However, treatment is far from
antibody specific and is not even specific to the disease
subgroup. Many new and more traditional drugs that
have not been tested properly in myasthenia gravis
have modes of action that are expected to suppress
autoantibody production directly or indirectly, and
therefore might benefit patients with myasthenia
gravis. For patients with severe symptoms that do not
 adapted treatment approach based on biomarker
(autoantibody) assessment and monitoring. The aim
Search strategy and selection criteria should be to suppress the anti- AChR, anti-MUSK, or
We searched MEDLINE and the Cochrane Library with the anti-LRP4 immune response without affecting other
terms “myasthenia gravis”, “myasthenic syndromes”, and immune reactions. An alternative approach could be
“myasthenia” from January 1995, to April, 2015. Guideline treatment that promotes tolerance to the antigens
and review papers were assessed in detail, and controlled (AChR, MUSK, and LRP4) that induce myasthenia
studies sought for in particular. Papers were selected by gravis.112 Patients with myasthenia gravis without
title and abstract. Only papers in English were included. detectable antibodies probably have pathogenic
Randomised trials on established and emerging therapies antibodies against undefined antigens in the
for myasthenia gravis are often scarce, so our neuromuscular junction; many proteins affect AChR
recommendations are based on the best available evidence or function, synthesis, and maintenance that could
clinical experience, where stated. potentially underlie antibody-negative disease. Auto-
immune myasthenia gravis with a T-cell-mediated and
autoantibodies and no non-antibody mechanism affecting neuromuscular
comorbidity as the symptom transmission could theoretically exist.
cause, such drugs could be When the causes of myasthenia gravis can be
tried, off-label, and with strict identified, they might be possible to avoid or prevent,
monitoring. These include potentially, for example, by vaccination. Until antigen-
monoclonal antibody drugs specific treatment is available, however, research
with a proven effect for other efforts should target new
autoimmune disorders.
Complement inhibition is one of
several potential strategies,76
with a focus on several factors
in the complement system.
Eculizumab, belimumab,
leflunomide, and etanercept are
drugs that might have the
potential to become new
myasthenia gravis treatment
options,76,107–109 although some
immunoactive drugs can
precipitate or worsen
myasthenia gravis.110 Tirasemtiv
(CK-2017357) selectively
sensitises fast skeletal muscle to
calcium by binding to its
troponin complex and amplifies
the muscle response when
neural input is diminished
secondary to neuromuscular
disease.111 A dose-related, short-
term improvement was
reported in a phase 2a
randomised placebo-controlled
trial.77 Any functionally relevant
long-term benefit to patients is
still to be proven. Several non-
antibody factors linked to the
immune system and skeletal
muscle affect the individual’s
muscle strength and immune
responses, and thereby each
patient’s myasthenia gravis
manifestations.
The high number of factors
associated with muscle
function in myasthenia gravis
should drive future research
towards an individually
 18 Skeie GO, Mygland A, Treves S. Ryanodine
receptor antibodies in myasthenia gravis:
immunosuppressive drugs and drug combinations for epitope mapping and effect on calcium
the myasthenia gravis subgroups. Prospective and release in vitro. Muscle Nerve 2003; 27:
controlled studies should be encouraged and 81–89.
supported. Severe myasthenia gravis is a reversible 19 Romi F, Aarli JA, Gilhus NE. Myasthenia
gravis patients with ryanodine
disorder that should be treated with intensity and receptor antibodies have distinctive
optimism. clinical features. Eur J Neurol 2007;
14: 617–20.
Contributors
NEG planned the Review and wrote the first draft. JJV edited and
rewrote the first draft. Both authors searched primary sources for
information, produced tables and figures, and finalised the text.
Declaration of interests
NEG has received speaker’s honorarium from Octapharma, Baxter, and
Merck Serono. JJV is a partner in an FP7 European grant that is associated
with Curavac. The Department of Neurology at Leiden University Medical
Center has received fees from BioMarin for JJV’s consultancy work and
royalties from antibody tests. JJV received research grants from Prinses
Beatrix Spierfonds and National Institutes of Health.
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Pediatric Myasthenia Gravis
Jason H. Peragallo, MD*,†

Myasthenia gravis is a disorder of neuromuscular transmission that leads to fatigue of skeletal

muscles and fluctuating weakness. Myasthenia that affects children can be classified into the
following 3 forms: transient neonatal myasthenia, congenital myasthenic syndromes, and juvenile
myasthenia gravis (JMG). JMG is an autoimmune disorder that has a tendency to affect the
extraocular muscles, but can also affect all skeletal muscles leading to generalized weakness and
fatigability. Respiratory muscles may be involved leading to respiratory failure requiring ventilator
support. Diagnosis should be suspected clinically, and confirmatory diagnostic testing be
performed, including serum acetylcholine receptor antibodies, repetitive nerve stimulation, and
electromyography. Treatment for JMG includes acetylcholinesterase inhibitors, immunosuppressive
medications, plasma exchange, intravenous immunoglobulins, and thymectomy. Children with
myasthenia gravis require monitoring by a pediatric ophthalmologist for the development of
amblyopia from ptosis or strabismus.
Semin Pediatr Neurol 24:116-121 C 2017 Elsevier Inc. All rights reserved.

Introduction
The myasthenic syndromes are due to defects of transmission
at the neuromuscular junction. Myasthenic syndromes in
children have 3 distinct forms with pathophysiologically
different mechanisms. The congenital myasthenic syndromes
(CMS) are a group of genetic disorders that lead to muscle
weakness through structural or functional abnormalities of the
proteins involved in neuromuscular transmission itself.
Transplacental transfer of maternal antibodies of a myasthenic
mother causes transient neonatal myasthenia (TNM) in infants.
Juvenile myasthenia gravis (JMG) is an autoimmune disorder
that leads to dysfunction of acetylcholine receptors (AChR). All
forms of myasthenia lead to muscle fatigue and weakness of
varying degrees. Fluctuations in weakness are a hallmark of
this disease. If weakness involves the musculature involved in
respiration, these diseases can be life threatening.1,2 This
review will focus primarily on the JMG form.
From the *Department of Ophthalmology, Emory University School of
Medicine, Atlanta, GA.
†
Department of Pediatrics, Emory University School of Medicine, Atlanta, GA.
Supported in part by an unrestricted departmental Grant (Department of
Ophthalmology) from Research to Prevent Blindness, Inc, New York,
and by NIH/NEI core Grant P30-EY06360 (Department of
Ophthalmology).
Address reprint requests to Jason H. Peragallo, MD, Department of Ophthal-
mology, Emory University School of Medicine, 1365B Clifton Rd NE, Atlanta,
GA 30322. E-mail: jperaga@emory.edu
Pathophysiology
In normal synaptic transmission in the neuromuscular junc- tion,
the axon is depolarized and this depolarization travels to the axon
terminal. Voltage-gated calcium channels open, leading to
acetylcholine containing vesicles to fuse to the cell membrane.
Acetylcholine is then released from synaptic vesicles into the
synaptic cleft from the axon terminal. The acetylcholine travels
across the synaptic cleft to the AChR sites where binding causes
sodium channels to open, depolarizing the motor end plate of the
muscle fiber. Acetylcholinesterase degrades the acetylcholine, and
the sodium channels close, allowing repolarization of the muscle
fiber.
Congenital Myasthenic Syndromes
The CMS are not autoimmune diseases, but are a group of
disorders caused by alterations in the structure or function of
proteins in the neuromuscular junction. These disorders must
be suspected to distinguish them from myopathies or other
neurogenic conditions.3 The disease can be the result of, for
example, inability to form normal acetylcholine, inability to
transport and release acetylcholine, abnormal nicotinic AChR,
primary AChR decifiency, end plate development and main-
tenance protein abnormalities, defects in protein glycosylation,
and many others.4 The most common cause of CMS is
alterations in the structure, presence, or kinetics of the AChR
itself.4 Performing a genetic analysis for the specific mutation
causing CMS is necessary to direct treatment for that specific

116 http://dx.doi.org/10.1016/j.spen.2017.04.003
1071-9091/11/& 2017 Elsevier Inc. All rights reserved.
Pediatric myasthenia gravis
syndrome. A treatment modality for CMS caused by one
mutation may actually be harmful to the patient if a
different mutation is present, and treatment must be
tailored to the specific mutation causing CMS. Children
with CMS often will have a relative who is similarly
affected. They will present with fatigable weakness, usually
at a very early age, and can present in infancy. The affected
muscles may be ocular alone, which can lead to isolated
fatigable ptosis, or all skeletal muscles may be affected
leading to more widespread weakness. Investiga- tions for
autoantibodies found in JMG and TNM will be negative.
Making the distinction between CMS and JMG may be
difficult if a known genetic mutation causative for CMS
cannot be identified and autoantibodies leading to JMG are
not detected.
Transient Neonatal Myasthenia
TNM is an antibody-mediated disorder that differs from
JMG and CMS. This disease presents shortly after birth in
infants of mothers who have autoimmune myasthenia
gravis. The circulating maternal autoantibodies cross the
placenta to the fetus, leading to an affected child after birth.
Children of mothers who have myasthenia gravis will
develop TNM approximately 5%-30% of the time.5,6 Infants
can present with generalized hypotonia, feeble cry,
respiratory distress, poor suck, and extraocular muscle
weakness.6 Symptoms are usually self-limited but
respiratory support may be necessary. Patients respond
well to neostigmine treatment and plasma exchange. TNM
can be distinguished from CMS by the detection of
autoantibodies, and when the disease is demon- strated to
be transient once autoantibodies are cleared from the
infant and symptoms resolve. No long-term treatment is
required once the autoantibodies are no longer present.
Juvenile Myasthenia Gravis
Juvenile myasthenia gravis is an autoimmune disorder pre-
senting with fatigability before the age of 19 years, which in
contrast to the CMS is not due to a structural abnormality in
the neuromuscular junction.7 JMG is also not a transient
disease, such as TNM. Autoantibodies against targets such
as the AChR and muscle-specific kinase (MuSK) lead to
decreased AChR activity though complement-mediated
lysis of the postsynaptic membrane, increased rate of
degradation of the receptor, and direct inhibition of
activity.8-10 Lipoprotein receptor–related membrane
protein 4 (LRP-4) is another target of autoantibodies
implicated in the development of myasthenia gravis in
patients in whom the antibodies to the AChR or MuSK were
not detected.11 LRP-4 is a protein necessary for MuSK
activation.12 Up to 18.4% of patients who do not have
antibodies to the AChR or MuSK were found to have
antibodies to LRP-4 in one analysis.12 Other autoimmune
diseases, such as Hashimoto disease and autoimmune
polymyositis, may be present in the same individual who
has JMG.13 A recent study analyzed data from patients who
had both myasthenia gravis and aquaporin 4 antibody–
positive neuromyelitis optica.14 In this study, 20% of
patients had JMG before developing neuromyelitis optica.14
As JMG is a
11
7
B-cell–mediated disease, recent studies have proposed B-cell–
activating factor as playing a role in its pathogenesis and as a
marker of disease activity in JMG.15,16
Demographics
There have been varying estimates of the incidence of
myasthenia gravis occurring in the general population in
the literature ranging from 1.7-30.0 cases per million
person years, with a prevalence of 77.7 cases per million
persons.17,18 Many studies estimating the incidence and
prevalence of JMG have also been published. A meta-
analysis of the literature on this subject concluded that the
incidence of JMG is approximately between 1.0 and 5.0
cases per million person years.17 Pediatric patients were
found to make up approximately 10%-15% of all patients
with autoimmune myasthenia gravis in a prevalence study
in Virginia.19 Among Asian populations, there appears to be
a higher prevalence of JMG compared to white populations,
with JMG representing up to 50% of all autoimmune
myasthenia gravis cases.20,21
Clinical Presentation
Fatigable skeletal muscle weakness that fluctuates is the
characteristic sign of myasthenia gravis. Myasthenia gravis is
known to preferentially target the extraocular muscles. Cases
in which only the extraocular muscles are affected are termed
ocular myasthenia gravis (OMG). If any other skeletal muscles
are involved, the patient is diagnosed with generalized
myasthenia gravis. The vast majority of patients who have
myasthenia gravis will have involvement of the extraocular
muscles at some point during the course of their disease.
Ocular Myasthenia Gravis
Approximately 10%-35% of all cases of JMG are of the
OMG subtype.1,22 OMG is a more common form of JMG in
Asian populations than in other populations.20,21 The
muscles involved include the vertical and horizontal rectus
muscles, inferior and superior oblique muscles, orbicularis
oculi, and the levator palperae superioris. The initial
presentation in these children may be ptosis, strabismus, or
diplopia. In one community-based case-control study, JMG
was the underlying cause of ptosis in 0.81% of pediatric
patients.23 JMG was present in children with ptosis at 26.7-
fold the rate of children who did not have ptosis.23 Patients
may actually have eyelid retraction, most prominent upon
awakening, of the eyelid that is found to be ptotic in the
clinic. Directed questions about ptosis should address not
only if it is worse in the evenings, but also if it appears
resolved upon awakening in the morning.
Patients with JMG with or without the purely ocular
form of disease can present with pseudo-cranial nerve
palsies, and may have variable strabismus measurements
when presenting to a pediatric ophthalmologist for
evaluation for strabismus sur- gery. It is important to note
that the pupils are not involved to a clinically detectable
degree in myasthenia gravis, distinguishing
this disease from other neurologic causes of strabismus.
Pupillary abnormalities should prompt evaluation for other
neurological causes. Rates of progression from OMG to
generalized myasthenia gravis has been reported from 8%-
49%, with rates of conversion for JMG specifically ranging
from 8%-33%.2,24-29 Preadolescent patients with OMG may
be less likely to progress to the generalized form than
adolescents.25
Generalized Myasthenia Gravis
The generalized form of JMG can be life threatening, as any
skeletal muscle can be involved, including the muscles
involved in respiration. If this occurs, patients may develop
respiratory failure requiring intubation.1,8 Presenting signs can
include the ocular motility abnormalities and ptosis described
earlier, but must include other limb or facial weakness,
difficulty breathing or swallowing, and chocking. Speech can
be affected leading to a change in voice characteristics.
Severity of myasthenia gravis can be classified according to the
Myasthenia Gravis Foundation of America’s classification
system, which allows for uniform criteria to be used cross-
institution for research purposes and for monitoring disease
severity.30
Diagnosis
Making the diagnosis of myasthenia gravis begins when a
patient demonstrates some form of fatigable weakness. A
thorough targeted clinical examination should include some
evaluation of fatigability to address suspicion of myasthenia
gravis. Ancillary testing for its diagnosis includes serologic,
pharmacologic, and electrophysiologic testing.
Clinical Examination Techniques
Fatigability on sustained upgaze is one of the simplest tests
to perform on patients in whom JMG is suspected. First,
palpebral fissure height is taken and an extraocular
motility examination is performed. The patient is then
directed to look at a target above their heads, and
instructed to look at the target without moving their head
out of primary position. The target is held there for a
certain period while the eyelid and ocular alignment is
closely observed. Patients with JMG may demonstrate a
change in palpebral height and ocular alignment while
being observed, which suggests fatigability. The target can
then be removed, and the ocular motility examination and
measurement of palpebral fissure height can be repeated.
Changes in these measurements suggest the presence of
myasthenia gravis.
The Cogan lid twitch is another feature that can be seen
in patients who have levator palpebrae superioris
involvement leading to ptosis. This sign can be elicited by
having a patient look in downgaze for a certain period,
followed by asking them to quickly look up. The eyelid
overelevates briefly (this is the “twitch”), followed by
fatigue and return to a ptotic position.
Having the patient look in downgaze causes relative rest of
the levator palpebrae, which is “overstimulated” upon
upgaze.
Another simple in office test that can suggest myasthenia
gravis if positive is the ice pack test. After measuring the
initial palperbral fissure height, an ice-filled glove or ice
pack is placed over the patient’s eye or eyes. The ice is left
there for 1-2 minutes while the patient rests. Once the ice is
removed, the palpebral fissure is measured again. An
improvement of ptosis of 2 mm of more is a positive result.
This test has been found to be approximately 80%
sensitive for the detection of myasthe- nia gravis.31,32 An
alternative to the ice pack test is the rest test, in which a
patient is asked to rest for 30 minutes after being
examined. Following a period of rest, the examination is
repeated, and measurements compared.33 The ice pack test
may be more sensitive than the rest test for the detection of
myasthenia gravis.34
Serologic Testing
Acetylcholine receptor antibody testing is readily available
commercially. The 3 main AChR antibodies tested are
binding, blocking, and modulating antibodies. Their
presence is important as it can definitively make the
diagnosis of myas- thenia gravis in uncertain cases.8,35 One
study of patients with JMG found an AChR antibody
positivity rate of 72% of those presenting with generalized
symptoms, and 41% in those presenting with ocular
symptoms alone.36 Patients who were initially AChR
antibody negative became positive 41% of the time within
2 years.36 However, most of those patients who converted
to positive AChR antibody status did not have worsening of
symptoms. Remission was associated with conversion from
AChR antibody positive to AChR antibody–negative status.36
Another more recent study found an AChR antibody
positivity rate of 86% in patients with JMG.22 The finding
that patients with the ocular form have autoantibodies to
the AchR less frequently than the generalized form is
similar to what is found in adults.37 Patients who are
negative for AChR antibodies can also be tested for anti-
MuSK antibodies, which have been found to be positive in
up to 40% of all patients with autoimmune myasthenia
gravis who are AChR antibody negative.38 Similar rates
have been found in AChR antibody–negative JMG series.39
Children who have anti-MuSK antibodies tend to have more
severe, acute, generalized symptoms, with respiratory
distress, similar to what is found in adults with anti-MuSK
antibodies.39,40 Response to treatment for JMG due to anti-
MuSK antibodies can be variable.39 Patients who are
negative for both AChR antibodies and MuSK antibodies but
clinically have myasthe- nia gravis are called “double
seronegative”. Another antibody that has been found to be
positive in double-seronegative patients is the lipoprotein
receptor-related membrane protein 4 (LRP-4).41 Pediatric
patients may be affected in anti-LRP- 4–mediated
myasthenia gravis as well.12 The incidence of anti-LRP-4
positivity varies widely from study to study, likely due to
different assays used by research teams.42 Anti-LRP-4–
associated myasthenia gravis tends to manifest mild
symptoms.12,41,42
 Pharmacologic Testing
The classic pharmacologic test for myasthenia gravis uses a
short-acting antiacetylcholinesterase, edrophonium, in the
edrophonium (Tensilon) test. By inhibiting acetylcholinester-
ase, the amount of acetylcholine is effectively increased in the
neuromuscular junction, and acetylcholine is able to bind to
the AChR for a longer period, leading to improved neuro-
muscular transmission. This test is performed with cardiac
monitoring and cardiopulmonary resuscitation equipment
(including atropine) readily available owing to the risk of
bradycardia and asystole. During the test, attention should be
directed to a sign of myasthenia the patient exhibits (muscle
weakness, ptosis, etc) that can be readily monitored. Compar-
ison to photographs can be useful. A small dose is given
initially to test for supersensitivity to edrophonium, followed
by escalating doses. Parasympathetic side effects including
excessive salivation, hypotension, diarrhea, flushing, nausea,
and sweating can occur. False negatives and false positives can
occur with edrophonium testing as other diseases can respond
to this test, or the patient may fail to respond to it.1 Neo-
stigmine is an alternative drug to edrophonium that can be
used in young children. Another alternative is to simply treat
the patient with a trial of pyridostigmine and observe for
improvements in symptoms over time.
Electrophysiological Testing
Two methods of electrophysiological testing are primarily
used for diagnosing myasthenia gravis. In one test, repetitive
nerve stimulation, trains of stimuli are delivered to a target
muscle, and quantitative analysis of the motor responses is
performed. A decremental response of 10% from the first to
the fourth response is considered a positive result.43 This test
is more sensitive in patients who have generalized JMG in
comparison to those who have ocular JMG.44 Currently the
“gold-standard” for testing for neuromuscular junction
disorders is single-fiber electromyography (sfEMG) performed
on the orbicularis oculi.43 The sfEMG is particularly useful in
cases of suspected myasthenia gravis with negative serologies
as it has very high sensitivity for MG.45 Unfortunately,
traditional single-fiber EMG studies are difficult to perform on
children due to discomfort and the length of the test. As an
alternative, a less invasive test termed stimulated single-fiber
EMG has been developed that can be used in children.43,46
Treatment
Acetylcholinesterase Inhibitors
Pyridostigmine is the main pharmacologic agent used in the
treatment of myasthenia gravis, whether in children or
adults. Edrophonium has too short a half-life to be of use in
long-term treatment of myasthenia gravis. Even with the
appropriate usage and dosing of pyridostigmine, symptoms
and signs of myasthenia gravis may continue.1
Pyridostigmine may be combined with other agents such
as immunosuppressives. Side effects of pyridostigmine are
similar to those of edropho- nium described earlier.
Immunosuppressive Agents
The most common immunosuppressive agent prescribed
for myasthenia gravis is prednisone. This medication is
easily administered orally to children with JMG, but long-
term use can be harmful due to systemic side effects.1
Children treated with prednisone demonstrated a good
overall response in a retrospective study.47 Additionally,
treatment with pre- dnisone has been found to have a
protective effect on the conversion from ocular to
generalized myasthenia.48,49 Treatment with prednisone
appeared to provide control of OMG in a randomized
clinical trial compared with placebo.50
Azathioprine can be considered for use in myasthenia
gravis. Children who do not have an adequate response to
steroids and anticholinesterase treatment can be placed on
azathio- prine, and it can be used as a steroid-sparing
agent.2,51-53 It should be kept in mind that azathioprine has a
delayed treatment effect from time of initiation of therapy,
is potentially teratogenic, and is considered
carcinogenic.52,54
Other immunomodulatory medications can be
considered for use in myasthenia gravis. Rituximab has
been found to be effective in its treatment, improve
symptoms, and reduce the amount of steroids required for
treatment.55-57 Rituximab has also been found to be effective
for long-term treatment of refractory myasthenia gravis.58
Mycophenolate mofetil has also been found to be effective
in the treatment of myasthenia gravis, but randomized
control trials have not demonstrated the ability to taper
steroids while on this agent.59-61 However, discontinuation
of mycophenolate mofetil in patients taking this medication
does lead to more frequent myasthenia gravis
exacerbations.62 Tacrolimus has been used for the
treatment of myasthenia gravis as well, including JMG.63,64
Other Medical Treatment Modalities
Intravenous immunoglobulin (IVIG) can be administered
for myasthenia gravis in an effort to reduce the
circulating autoantibodies by decreasing B-cell antibody
production and T-cell function. In a randomized
controlled trial against placebo, IVIG was found to be
effective in improving myasthenia gravis symptoms.65
Therapy with IVIG has been used for patients with JMG,
but appeared to have better efficacy for short-term
treatments and exacerbations than for long-term
treatment.66,67 Plasmapheresis can also be used in
patients with myasthenia gravis to directly filter
autoantibodies and cytokines from the affected patient’s
serum. A comparison in patients with JMG between IVIG
and plasmapheresis for maintenance therapy
demonstrated high response rates for both modalities,
but a more consistent response with plasmapheresis. 68
However, pre- vious studies performed in adults have
shown no signifi- cant difference between the 2
treatments.69 Consensus statements state that IVIG and
plasmapheresis are appro- priate for acute
exacerbations or crises only, and are not appropriate for
maintenance therapy unless patients are unable to
tolerate immunosuppressive agents or have refractory
myasthenia gravis.70
 Thymectomy
Approximately 10%-15% of all adults with myasthenia
gravis are found to have a thymoma, and 30% of patients
who have a thymoma develop myasthenia gravis. 71,72
Children who have myasthenia gravis have rarely been
found to harbor thymo- mas.22,73 However, thymectomy for
patients with seropositive JMG has been evaluated and has
been found to be associated with improved remission
rates.22,74 Therefore, thymectomy may have a role for
children who are unresponsive to medical therapy or who
cannot undergo standard immunsuppression, although the
long-term effects of thymectomy in children are unclear.70
Thymectomy may protect patients with the ocular form of
JMG from undergoing generalization, and may improve
ocular symptoms as well.9,24 A randomized trial of
thymectomy for adult patients on prednisone for
myasthenia gravis demonstrated a reduction in prednisone
dose require- ment and improvement in symptoms for
those who under- went thymectomy.75
Ophthalmic Outcomes
Patients with JMG should be monitored for the
development of amblyopia and strabismus.76 Amblyopia
should be treated to prevent permanent vision loss. Up to
96% of patients with the ocular form of JMG will have
ptosis, and up to 88% will present with strabismus.28
Amblyopia has been found in 21%- 50% of children with
ocular JMG, but following properly diagnosis and treatment,
that proportion of patients with amblyopia has been found
to decrease as low as 3%.24,25,28 Strabismus is more difficult
to treat in patients with ocular JMG, with its presence at
final follow-up ranging from 15%- 57%.24,25 Ptosis may
remain in patients who have stable disease in 46%-66% of
patients.24,25 Upon stabilization of the underlying disease,
surgical correction of the strabismus and ptosis can be
considered, with a 56% long-term success rate found in
one retrospective study.77 Counseling should be given
about realistic expectations of strabismus surgery and
about the possibility of requiring multiple surgical
interventions.
Conclusions
Pediatric myasthenia gravis can present as neonatal
myasthenia gravis (CMS, TNM) or during adolescence
(JMG). The latter is an autoimmune disease that can have a
variable presentation, ranging from mild ophthalmic
symptoms, such as isolated fatigable ptosis, to myasthenic
crises involving the respiratory muscles, requiring
ventilator support. Making a formal diag- nosis of the
disease can be difficult, but when suspicion is raised for a
fatigable deficit, appropriate diagnostic testing can be
pursued. Treatments should be tailored to the subtype of
disease and the severity of illness. Variable responses to
medications and surgical interventions can be seen
between patients. Children with involvement of the
extraocular mus- culature should be followed by a pediatric
ophthalmologist to monitor for ophthalmic complications
associated with JMG.
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62. Oskarsson B, Rocke DM, Dengel K, Richman DP: Myasthenia
gravis exacerbation after discontinuing mycophenolate. Neurology 86: 1159-1163, 2016

63. Minami N, Fujiki N, Doi K, et al: Five-year follow-up with low-dose

tacrolimus in patients with myasthenia gravis. J Neurol Sci 300:59-62, 2011

64. Mori T, Mori K, Suzue M, et al: Effective treatment of a 13-year-old boy with steroid-dependent ocular myasthenia gravis using tacrolimus.
Brain Dev 35:445-448, 2013
65. Zinman L, Ng E, Bril V: IV immunoglobulin in patients with myasthenia
gravis. Neurology 68:837-841, 2007

66. Selcen D, Dabrowski ER, Michon AM, Nigro MA: High-dose intravenous immunoglobulin therapy in juvenile myasthenia gravis. Pediatr Neurol
22:40-43, 2000
67. Feasby T, Banwell B, Benstead T, et al: Guidelines on the use of
intravenous immune globulin for neurologic conditions. Transfus Med Rev 21:S57-S107, 2007

68. Liew WK, Powell CA, Sloan SR, et al: Comparison of plasmapheresis and
intravenous immunoglobulin as maintenance therapies for juvenile myasthenia gravis. JAMA Neurol 71:575-580, 2014

69. Gajdos P, Chevret S, Toyka KV: Intravenous immunoglobulin for

myasthenia gravis. Cochrane Database Syst Rev 12:CD002277, 2012

70. Sanders DB, Wolfe GI, Evoli A, et al: International consensus guidance for management of myasthenia gravis. Neurology 87:419-425, 2016
71. Marx A, Pfister F, Schalke B, et al: The different roles of the thymus in the pathogenesis of the various myasthenia gravis subtypes. Autoimmun
Rev 12:875-884, 2013
72. Gilhus NE, Verschuuren JJ: Myasthenia gravis: Subgroup classification and therapeutic strategies. Lancet Neurol 14:1023-1036, 2015
73. Nikolic DM, Nikolic AV, Lavrnic DV, et al: Childhood-onset myasthenia gravis with thymoma. Pediatr Neurol 46:329-331, 2012
74. Heng HS, Lim M, Absoud M, et al: Outcome of children with
acetylcholine receptor (AChR) antibody positive juvenile myasthenia gravis following thymectomy. Neuromuscul Disord 24:25-30, 2014

75. Wolfe GI, Kaminski HJ, Aban IB, et al: Randomized trial of thymectomy in
myasthenia gravis. N Engl J Med 375:511-522, 2016

76. Emoto Y, Emoto H, Fujie W, Wakakura M: Prolonged constant eye misalignment leads to failure to develop binocular vision in childhood ocular
myasthenia gravis. J Pediatr Ophthalmol Strabismus 46:358-361, 2009
77. Peragallo JH, Velez FG, Demer JL, Pineles SL: Long-term follow-up of
strabismus surgery for patients with ocular myasthenia gravis. J Neuro- ophthalmol 33:40-44, 2013
 CMScri
Member of a medical scheme? Know your guaranteed benefits!

pt Issue 5 of 2017

Myasthenia
Gravis
Myasthenia Gravis (MG) is a Chronic Autoimmune Neuromuscular condition that causes weakness in cer- tain
muscles of the body. MG is caused by an error in the transmission of nerve impulses to the muscles. In MG
the immune system makes antibodies that mistakenly attack the connections between nerves and muscles
preventing muscles from contracting and resulting in weakness.

What does
autoimmune
mean? The immune
system (the body’s in-
fection-fighting technique)
normally makes proteins
called “antibodies,” which
help to prevent or fight
infec- tion.

Antibodies are proteins

made by the body’s immune
system when it de- tects
harmful substances.
Antibodies may be produced
when the immune system
mistakenly considers
 healthy tissue as harmful
substance.

What is the neuromuscular

junction?
The Neuromuscular junction is the
meeting point of a nerve cell and
the muscle it controls.
Communication
happens between the nerve and muscle fibers through
the nerve cells called neurons. Due to this communica-
tion or transmission of signal, the muscle is able to con-
tract or relax. When the muscles contract, Acetylcholine
gets released by the nerve cells. Acetylcholine acts as a
chemical messenger that causes our skeletal muscles to
contract. The diagram above right shows the neuromus-
cular junction.
What causes Myasthenia Gravis?
MG is caused by an error in the transmission of nerve im-
pulses to the muscles. In MG the immune system makes
antibodies that mistakenly attack the connections between
nerves and muscles preventing muscles from contracting
and resulting in weakness. The diagram on the next page
shows the antibodies attacking the junction between nerves
and muscle.
Some people may have Myasthenia Gravis that is not caused
by antibodies blocking Acetylcholine or the mus- cle-
specific receptor tyrosine kinase. This type of condition is
called antibody-negative Myasthenia Gravis.
The role of thymus gland in myasthenia gravis
The thymus gland, lies in the chest area beneath the
breastbone (sternum), and plays an important role in the
development of the immune system in early life. Its cells
form part of the body’s normal immune system. The gland

Figure 1: The neuromuscular

junction

Figure 2: Antibodies attacking the junction between nerves and
muscle.
is somewhat larger in infants, grows gradually until puberty, and
then gets smaller and is replaced by fat with age. In adults with
Myasthenia Gravis, the thymus gland remains large and is
abnormal. Some individuals with Myasthenia Gravis develop
thymomas (tumors of the thymus gland).
The relationship between the thymus gland and Myasthenia
Gravis is not yet fully understood. Scientists believe that the
thymus gland may give incorrect instructions to developing
immune cells, ultimately resulting in autoimmunity.
What happens if I have Myasthenia Gravis?
The hallmark of Myasthenia Gravis is muscle weakness that
increases during periods of activity and improves after periods of
rest. Certain muscles such as those that con- trol eye and eyelid
movement, facial expression, chewing, talking, and swallowing are
often, but not always, involved in the disorder. The muscles that
control breathing and neck and limb movements may also be
affected.
These include:
• Muscles in the eyelids and around the eyes – If
MG only affects these muscles, doctors call it
“ocular my- asthenia gravis.” About half of all
people with MG have this type.
2 CMScript
5/2017
• Jaw muscles
• Arm or leg muscles
• Muscles that help with breathing
What are the symptoms of Myasthenia
Gravis? The main symptom is muscle weakness. It
can come and go, and is often worse later in the
day. This can result in:
• Ptosis (Droopy eyelids).
• Diplopia (Blurry vision or double vision).
• Trouble chewing food - The jaw muscles might
feel tired about halfway through a meal.
• Trouble swallowing.
• Dysarthria (Trouble talking) – A person might
speak in a lower voice than usual, or sound like
he or she has a cold or stuffy nose.
• Loss of expression on the face.
• Head that feels heavy or drops forward.
• Trouble breathing – A person might feel short
of breath, take extra breaths, or feel like it
takes a lot of effort to breathe.
• Weakness – It might be hard to lift the arms or
legs, open the fingers, or lift a foot.
Who gets Myasthenia Gravis?
Myasthenia Gravis occurs in all ethnic groups and both genders.
It most commonly affects young adult women (under 40) and
older men (over 60), but can also occur at any age. The
condition is not directly inherited nor is it contagious.
What is covered under PMB level of care?
PMBs refer to the benefits as stated in Section 29 (1) (o) of the
Medical Schemes Act, No. 131 of 1998 (the Act) Myasthenia
Gravis is a PMB condition under Diagnosis and Treatment Pair
(DTP) code 513A.
This DTP refers to Myasthenia gravis as muscular dystro- phy;
neuro-myopathies NOS. The treatment component specified for
this DTP according to the PMB Regulations is Initial diagnosis;
initiation of medical management; therapy for acute
complications and exacerbations. The following should
therefore be paid according to the PMB Regulations:
Diagnosis
The doctor will record the patient’s medical history, do a
physical and detailed neurological examination to under- stand
the symptoms. If the doctor suspects Myasthenia Gravis, several
tests can be performed to confirm the di- agnosis. Not all
patients qualify for all the tests mentioned below. The
investigations are done subject to the discre- tion of the treating
doctor.
 The tests can include: hyperplasia of the thymus gland.
• Blood tests for certain antibodies that are found • Treatment options also include
in peo- ple with MG such as acetylcholine methotrexate, myco- phenolate mofetil and
receptor antibodies. cyclosporine.
• Electrical tests of nerves and muscles –
Repetitive nerve stimulation.This is a nerve As the PMB Regulations stipulate initiation of treatment, the
chronic use of the abovementioned treatments is not included
conduction study in which doctors attach and the medical scheme does not have to fund the chronic
electrodes to your skin over the muscles to be medicine in full.
tested. Doctors send small pulses of electricity
through the electrodes to measure the nerve’s
ability to send a signal to your muscle. To di-
agnose Myasthenia Gravis, doctors will test the
nerve many times to see if its ability to send
signals worsens with fatigue.
• Imaging tests, such as Computerized
Tomography (CT) or Magnetic Resonance
Imaging (MRI) scans – Imaging tests can show
changes, including a tumor on the thymus gland.
• Ice pack test – During this test, a doctor puts a
cool pack on the eyelids. If the eyelids open
better after rest- ing under the cool pack, this
could be a sign of MG.
• Pulmonary function testing - which measures
breathing strength, helps to predict whether
respiration may fail and lead to a Myasthenia
crisis.

How is Myasthenia Gravis treated?

Initiation of treatments, which may include:
• Medicines to treat muscle weakness, such as
pyr- idostigmine.
• Medicines that treat the immune system over
time, such as prednisone or azathioprine. These
medications im- prove muscle strength by
suppressing the production of abnormal
antibodies.
• Fast-acting immune system treatments, such as:
• A medicine called “intravenous immune
globulin” (IVIG) – high-dose intravenous
immune globulin, which temporarily
modifies the immune system by infusing
antibodies from donated blood.
• Plasma exchange (also called
“plasmapheresis”)
–a procedure in which serum containing the ab- normal
antibodies is removed from the blood while cells are
replaced.
• Surgery to remove the thymus gland in patients
with thymoma (tumor of the thymus gland /
abnormal tis- sue of the thymus gland) or

CMScript 3
Therapy for exacerbations and acute complications such as pneumonia
and respiratory failure must however be funded as PMB level of care
by the medical scheme. What else should I know about Myasthenia
Gravis? People who have MG that affects more than just the
These therapies may be used to help individuals during especially eyes can have serious problems if they get the flu or pneumonia.
difficult periods of weakness. A Neurologist will determine which For this reason, it is especially important that they get the flu
treatment option is best for each individ- ual depending on the severity vaccination every year and the pneumonia vaccine as per the
of the weakness, the kind of muscles are affected, as well as the national vaccination guideline.
individual’s age and other associated medical problems.
Some medicines can make MG worse. Talk to your doctor or nurse
If MG attacks the muscles that help with breathing, it can cause severe
before you take any medicines, including over-the- counter
breathing problems. These patients are usu- ally treated in the
medicines. If you get a prescription for a new med- icine, ask if it is
Intensive Care Unit (also called the “ICU”) and may require assisted
safe to take when you have MG.
ventilation.

Children with MG can take some of the same medicines prescribed for
adults, at age appropriate doses. However, some medicines used to
treat MG can cause more serious problems in children if used for a long
time. Surgery to re- move the thymus gland is safe for children and
often works well.
What is a Myasthenic crisis?
A Myasthenic Crisis occurs when the muscles that control breathing
weaken to the point that ventilation is inadequate, creating a medical
emergency and requiring a respirator for assisted breathing.
Respiratory failure is included in the PMBs and the medical scheme
must fund the medical treat- ment, oxygen and ventilation in full.
References
1. Choi, D. E., Hobson-Webb, L.D., & Juel, V.C.l.
(2014). Do acetylcholine receptor and striated
muscle antibod- ies predict the presence of
thymoma in patients with myasthenia gravis.
Muscle Nerve, 49:30.
2. Golnik, K.C., Pena, R., Lee, A.G. & Eggenberger,
E.R. (1999). An ice test for the diagnosis of
myasthenia gra- vis. Ophthalmology, 106:1282.
3. Krendel, D.A., Sanders, D.B., Massey, J.M. (1987).

Single fiber electromyography in chronic progressive external

ophthalmoplegia. Muscle Nerve, 10:299.
4. Mahadeva, B., Phillips, L.H. 2nd & Juel, V.C.
(2008). Autoimmune disorders of
neuromuscular transmission. Semin Neurol,
28:212.
5. Matell, G. (1987). Immunosuppressive drugs:
azathio- prine in the treatment of myasthenia
gravis. Ann N Y Acad Sci, 505:589.
6. Meriggioli, M.N., Sanders, D.B. (2009).
Autoimmune myasthenia gravis: emerging
clinical and biological heterogeneity. Lancet
Neurol, 8:475.
7. Milone, M., Monaco, M.L., Evoli, A. (1993).
Ocular my- asthenia: diagnostic value of single
fibre EMG in the orbicularis oculi muscle. Journal
of Neurol Neurosurg Psychiatry, 56:720.
WHAT ARE PRESCRIBED MINIMUM BENEFITS?
8. Muscle Study Group. (2008). A trial of mycophenolate
mofetil with prednisone as initial immunotherapy in my- Prescribed Minimum Benefits (PMBs) are defined by
asthenia gravis. Neurology, 71:394. law. They are the minimum level of
9. National Institute of neurological disorders and diagnosis,treatment, and care that your medical
stroke: Myasthenia Gravis scheme must cover – and it must pay for your PMB
10. Pascuzzi, R.M. (2003). The edrophonium test. condition/s from its risk pool and in full. There are
Semin Neurol, 23:83. medical interventions available over and above those
11. Sanders, D.B., Hart, I.K. & Mantegazza, R. (2008). prescribed for PMB conditions but your scheme may
An international, phase III, randomized trial of choose not to pay for them. A desig- nated service
mycophe- nolate mofetil in myasthenia gravis. provider (DSP) is a healthcare provider (e.g. doctor,
pharmacist, hospital) that is your medical scheme’s
first choice when you need treatment or care for a
4 CMScript PMB condition. You can use a non-DSP voluntarily or
 use a non-DSP, you may have to pay a portion of the
bill as a co-payment. PMBs include 270 serious health
conditions, any emergency condition, and 25 chronic
diseases; they can be found on our website
Neurology, 71:400.
12. Sanders, D.B., Wolfe, G.I. & Benatar, M. (2016).
Inter- national consensus guidance for
management of myas- thenia gravis: Executive
summary. Neurology, 87:419.
13. Sethi, K.D., Rivner, M.H. & Swift, T.R. (1987). Ice
pack test for myasthenia gravis. Neurology,
37:1383.
14. Vernino, S. & Lennon, V.A. (2004). Autoantibody
pro- files and neurological correlations of
thymoma. Clin Cancer Res, 10:7270.
15. Figure 1 -
http://www.mayoclinic.org/-/media/kcms/
gbs/patient-
consumer/images/2013/08/26/10/28/
ds00375_im00332_r7_receptorsthu_jpg.jpg
[Ac- cessed 12 June 2017]
16. Figure 2 -
http://www.chop.edu/sites/default/files/my-
asthenia-gravis-neuromuscular-junction-
illustration- 773x949.png [Accessed 12 June
2017]

From the Department of Clinical Medi-
cine, University of Bergen, and the Depart-
ment of Neurology, Haukeland University
Hospital — both in Bergen, Norway. Ad-
dress reprint requests to Dr. Gilhus at the
Department of Neurology, Haukeland Uni-
versity Hospital, 5021 Bergen, Norway, or at
nils.gilhus@uib.no.
N Engl J Med 2016;375:2570-81.
DOI: 10.1056/NEJMra1602678
Copyright © 2016 Massachusetts Medical Society.
T he NE W E NGL A ND JOU R NA L o f M E DIC INE
REVIEW ARTICLE
Dan L. Longo, M.D., Editor
Myasthenia Gravis
M Nils E. Gilhus, M.D.
YASTHENIA GRAVIS IS AN AUTOIMMUNE DISEASE IN WHICH ANTI- bodies bind to
acetylcholine receptors or to functionally related molecules in the postsynaptic membrane at
the neuromuscular junction. The anti-
bodies induce weakness of skeletal muscles, which is the sole disease manifesta- tion.1-3 The weakness
can be generalized or localized, is more proximal than dis- tal, and nearly always includes eye
muscles, with diplopia and ptosis.2 The pattern of involvement is usually symmetric, apart from the
eye involvement, which is often markedly asymmetric and involves several eye muscles. The
weakness typi- cally increases with exercise and repetitive muscle use (fatigue) and varies over the
course of a day and from day to day, often with nearly normal muscle strength in the morning.
With an annual incidence of 8 to 10 cases per 1 million persons and a preva- lence of 150 to
250 cases per 1 million,4 myasthenia gravis and its various sub- groups are the major diseases that
affect the neuromuscular junction. The Lambert– Eaton myasthenic syndrome and neuromyotonia are
additional, rare, presynaptic autoantibody disorders characterized by skeletal-muscle dysfunction.5
Congenital myasthenic syndromes and toxin-induced conditions (e.g., botulism) can also affect the
neuromuscular junction and lead to muscle weakness. This review focuses on new diagnostic tests for
myasthenia gravis, updated treatment algorithms, and individualization of therapy according to
biomarkers.
The diagnosis of myasthenia gravis is confirmed by the combination of relevant symptoms and
signs and a positive test for specific autoantibodies.6 Antibodies against acetylcholine receptors,
muscle-specific kinase, and lipoprotein receptor– related protein 4 (LRP4) are specific and sensitive
for the detection of myasthenia gravis, define disease subgroups, and point to pathogenic variations
among these subgroups. The localization of the antigens at the neuromuscular junction and in skeletal
muscle is shown in Figure 1. The disease-inducing potential of the anti- bodies depends on the
epitope, binding pattern, IgG subclass, antibody cross-linking capacity, antibody concentration, and
access of antibody to the muscle end plate.7 In antibody-negative cases, neurophysiological tests and a
characteristic re- sponse to therapy secure the diagnosis.8 An ice-pack test that reverses ptosis sup-
ports the diagnosis. Thymic status should be determined by means of mediastinal imaging.9 The main
value of such imaging is to detect a thymoma; this imaging is neither sensitive nor specific for the
identification of thymic hyperplasia. Sup- plementary antibody tests can provide further help in
characterizing the thymus.10 Symptomatic, immunoactive, and supportive approaches to therapy have a
very good effect, and the prognosis regarding muscle strength, functional abilities, quality of life,
and survival is generally good.11,12 Therapy should be aimed at full or nearly full pharmacologic
remission (i.e., the absence of myasthenic symptoms
and signs while the patient is receiving therapy).
 M YASTHENIA G R AVIS

MITOCHONDRION

Synaptic vesicle

MOTOR NEURON

Acetylcholinesterase
SYNAPTIC CLEFT
Inhibition improves
symptoms of
myasthenia gravis Acetylcholin
Agrin e
Antibody
targets

Antibody target
MuSK

Acetylcholine
receptor

LRP4 Dok7
Rapsyn

Antibodies as biomarkers

Ryanodine
receptor

MUSCLE CELL

SARCOPLASMIC RETICULUM

Antibodies as biomarkers

Titin

SARCOMERE

Figure 1. Neuromuscular Junction and Key Elements for the Pathogenesis of Myasthenia Gravis.

Neuromuscular transmission involves release of presynaptic acetylcholine, which binds to acetylcholine receptors in the
postsynaptic membrane. The receptors interact with several other proteins in the membrane, including Dok7 and rapsyn. Mutant
Dok7 and rapsyn are important in the development of congenital myasthenia. Antibodies against acetylcholine receptors, as well
as antibodies against muscle-specific kinase (MuSK) and lipoprotein receptor–related peptide 4 (LRP4), induce myasthenic weakness.
Antibodies against the intramuscular proteins titin and ryanodine receptor are relevant biomarkers in some subgroups of
myasthenia gravis. Acetylcholine is degraded by local acetylcholinesterase, and acetylcholinesterase inhibition leads to
symptomatic improvement in patients with myas- thenia gravis.

The New England Journal of Medicine

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Copyright © 2016 Massachusetts Medical Society. All rights reserved.
 N ENGL J MED 375;26 NEJM.ORG DECEMBER 29, 2016 2571

The New England Journal of Medicine

Downloaded from nejm.org at TULANE UNIV on January 16, 2019. For personal use only. No other uses without permission.
Copyright © 2016 Massachusetts Medical Society. All rights reserved.
 T he NE W E NGL A ND JOU R NA L o f M E DICI NE

C L I N IC A L A ND P A T HO GE N IC the immune system and probably the risks of

VA R I A N T S autoimmune disease; late-onset disease is asso-
ciated with HLA-DR2, HLA-B7, and HLA-DRB1
17,18
Variants of myasthenia gravis are defined on the basis 15.01. Thymic status and HLA pattern repre- sent
of autoimmune and antibody disease mech- anisms, strong subgroup markers, probably point- ing directly
target molecules of skeletal muscle, thymic status, to variation in pathogenic pathways. Early-onset
genetic characteristics, response to therapy, and myasthenia gravis is three times as likely to be
disease phenotype. Patients with myasthenia gravis diagnosed in females as it is in males, whereas
should always be subgrouped on the basis of all these males slightly outnumber fe- males in the late-
variables (Fig. 2A) and should be assigned to only onset group. Coexisting auto-
one subgroup. To
combine disparate clinical and nonclinical fea-
tures in the classification of individual patients is A Myasthenia Gravis Subgroups
a challenge (Table 1). Subgroups influence thera- peutic decisions and prognosis.
In 15% of all patients with myasthenia gravis,
symptoms and signs are confined to ocular
muscles. Only half of patients with ocular myas- thenia
Ocular
gravis have detectable muscle antibod- ies.13 Ptosis Early onset
and diplopia are common initial symptoms, but the
disease remains restricted to ocular muscles in only a Seronegative
minority of patients. In 90% of patients who
continue to have purely ocular myasthenia gravis 2
years after the start of symptoms, the disease will MuSK
persist as a focal eye-muscle weakness and never LRP4
Late onset
become general- ized. Myasthenia gravis with
Thymoma
muscle-specific kinase antibodies is not manifested
as ocular myasthenia, whereas both acetylcholine
receptor and LRP4 antibodies can be found in the
ocular subgroup.2 The presence of muscle
antibodies increases the risk of subsequent B Coexisting Conditions
generalized disease.
Ten percent of patients with myasthenia gra-
vis have a thymoma, and the prevalence increases with
Thymoma
increasing age. Two thirds of patients with
myasthenia gravis have generalized early-onset or
late-onset disease and no thymoma. Among patients
who have myasthenia gravis with acetyl- choline Autoimmunity
Therapy- Myasthenia
induced gravis
receptor antibodies, the age at onset has a bimodal disorders
pattern, supporting the use of a cutoff age of 50 years
to distinguish between early- onset and late-onset
disease.14 Juvenile myasthe- nia gravis, which is Cardiac
included in the early-onset group and is defined as Unrelated
disease
an onset before the age of 15 years, is much more disorders
common in East Asian populations than in whites.15,16
Early-onset myas- thenia gravis tends to be
characterized by thymic hyperplasia, whereas thymic
atrophy is charac- teristic of late-onset disease. Early-
onset myasthe- nia gravis is associated with HLA-DR3,
HLA-B8, and non-HLA genes that are known to Figure 2. Subgroups of Myasthenia Gravis and Coexisting
influence Conditions.
Panel A shows myasthenia gravis subgroups defined on
the basis of clinical, antibody, and thymic features. MuSK
2572 denotes muscle-specific kinase, and LRP4 lipo- protein
N ENGL J MED 375;26 NEJM.ORG DECEMBER 29, 2016
receptor–related protein 4. As shown in Panel B, patients
with myasthenia gravis commonly have coexist- ing
conditions that are related to their disease (especially
thymoma and other autoimmune conditions), induced by
therapy, or unrelated to their disease.
 M YASTHENIA G R AVIS
Table 1. Features of Myasthenia Gravis Subgroups.*
Subgroup Antibody
Early onset Acetylcholine receptor
Late onset Acetylcholine receptor
Thymoma Acetylcholine receptor
Muscle-specific kinase Muscle-specific kinase
LRP4 LRP4
Seronegative None detected
Ocular Variable
* LRP4 denotes lipoprotein receptor–related protein 4.
immune disorders are more common in early-
onset disease than in late-onset disease.19
Titin antibodies, which occur primarily in pa- tients
with a thymoma and late-onset myasthe- nia gravis, in
addition to acetylcholine receptor antibodies,10,20
have been shown to be a marker for severe disease.
Ryanodine receptor antibod- ies, which are present
in 70% of patients with a thymoma and myasthenia
gravis and in 14% of those with late-onset myasthenia
gravis,10 are a marker for more severe disease but
have no disease-modifying effects. Kv1.4 antibodies
are detected in 10 to 20% of patients with acetylcho-
line receptor antibodies.21,22 The disease pheno- type
does not differ between early-onset and late-onset
myasthenia gravis.
Myasthenia gravis with muscle-specific kinase
antibodies accounts for 1 to 10% of cases.23 This
disorder is more common in the Mediterranean area
of Europe than in northern Europe and is also
more common in the northern regions of East Asia
than in the southern regions.24 The reason for this
variation is thought to be a ge- netic predisposition
rather than environmental factors. Patients with
myasthenia gravis and muscle-specific kinase
antibodies, as compared with patients without these
antibodies, have more severe weakness, sometimes
with muscle atro- phy, and have marked symptoms
from facial and bulbar muscles. Limb weakness and
ocular weak- ness are less common and fluctuations in
muscle strength are less pronounced than in
disease characterized by acetylcholine receptor
antibodies. LRP4 antibodies are present in 1 to 3% of
all patients with myasthenia gravis.25,26 Such patients
tend to have only mild-to-moderate symptoms.
Neither cases of myasthenia gravis with LRP4
antibodies nor those with muscle-specific kinase
N ENGL J MED 375;26 NEJM.ORG
Age at Onset Thymus
<50 yr Hyperplasia common
≥50 yr Atrophy common
Any age Lymphoepithelioma
Any age Normal
Any age Normal
Any age Variable
Any age Variable
antibodies are associated with any proven thymic
disease. A few patients with muscle-specific ki- nase
or LRP4 antibodies in combination with
acetylcholine receptor antibodies have been de-
scribed.1,6 Such patients should be classified ac-
cording to the muscle-specific kinase or LRP4
antibodies.
In some patients with myasthenia gravis, no serum
antibodies against neuromuscular junction proteins can
be detected. After standard testing with
commercially available kits, 10 to 15% of patients
remain seronegative. Cell-based assays for antibody
detection are more sensitive than serum tests
because the antigens expressed on cell membranes
can be clustered and maintain their natural
conformation.27 Such cell-based assays have been
developed for acetylcholine re- ceptor, muscle-
specific kinase, and LRP4 anti- bodies.1,6 One third of
patients with generalized myasthenia gravis who are
seronegative on stan- dard testing are seropositive on
cell-based test- ing. The seronegative group probably
includes some patients with acetylcholine receptor,
muscle- specific kinase, or LRP4 antibodies that are
not detected because of insufficient test sensitivity.
Some patients may have pathogenic antibodies
against other postsynaptic membrane antigens. These
antigens interact with acetylcholine recep- tors. Some
patients may have disease that is not mediated by
antibodies.
Agrin antibodies, in the absence of other
muscle antibodies, have been found in a minor- ity of
patients with myasthenia gravis.28 These antibodies
seem to be specific for myasthenia gravis. Agrin
has regulatory properties in the postsynaptic
membrane and is linked to neuro- muscular
transmission, but so far, a pathogenic effect of agrin
antibodies has not been estab-
DECEMBER 29, 2016 2573
 T he NE W E NGL A ND JOU R NA L o f M E DICI NE
lished. Collagen Q and cortactin antibodies have been
detected in some patients.1,29 The specificity of these
antibodies for myasthenia gravis has been
questioned.
In seronegative patients with myasthenia gra- vis,
the diagnosis should be reevaluated, and anti- body
tests should be repeated after 6 to 12 months. Before
sensitive cell-based assays are included in clinical
practice, standard procedures for these assays, as well
as their disease specificity, need to be defined.
C O e x I S T I NG D I S OR DER S
Coexisting conditions are common in patients with
myasthenia gravis and should always be considered
(Fig. 2B). Approximately 15% of pa- tients have a
second autoimmune disease,19,30 which occurs most
frequently in patients with early-onset myasthenia
gravis and thymic hyper- plasia. Thyroiditis is the most
common coexist- ing condition, followed by systemic
lupus erythe- matosus and rheumatoid arthritis. In
patients with ocular myasthenia, thyroid disease is
espe- cially common.
Myasthenia gravis occurs in one third of all
patients with a thymoma. Although the strong
association between thymoma and myasthenia gravis
is unique, thymoma is also associated with an
increased risk of certain other autoim- mune
disorders. Blood cytopenias, hypogamma- globulinemia,
polymyositis, the POEMS syndrome (polyneuropathy,
organomegaly, endocrinopathy, M component, and skin
changes), neuromyotonia, and autoimmune
encephalitis occur with an in- creased frequency among
patients with a thymoma but are rare in patients with
myasthenia gravis. Neuromyelitis optica with
aquaporin-4 anti- bodies has a prevalence of 40 cases
per 1 million population,31 has a specific association
with myasthenia gravis, and can occur either before
or after the onset of myasthenia gravis.32 Amyo-
trophic lateral sclerosis (ALS) occurs in patients with
myasthenia gravis more often than would be
expected on the basis of the risk in the gen- eral
population. Autoimmune disease in general
represents a risk factor for ALS, but the association
with myasthenia gravis is especially strong.33,34
Myocarditis is rare but occurs with an in-
creased frequency in patients with myasthenia gravis,
as indicated by numerous single case series and
reports.35 However, myasthenia-related
2574
N ENGL J MED 375;26
clinical heart disease and heart dysfunction are very
rare. In population-based studies, myasthenia gravis
has not been associated with an increase in
mortality related to heart disease.36 Functional
imaging studies have shown minor and sub- clinical
dysfunction.37 Myocarditis in myasthenia gravis is
associated with Kv1.4 muscle antibod- ies.22 Antibodies
against acetylcholine receptor, muscle-specific kinase,
and LRP4 do not cross- react with heart muscle, in
contrast to nonjunc- tional antibodies against Kv1.4,
titin, and ryano- dine receptor.38
For the most part, patients with myasthenia
gravis do not seem to have any clinically relevant
increase in the risk of cancer.39,40 The exception is
the subgroup of patients with thymoma. The
increased cancer risk among patients with thy- moma
is the same whether or not they have myasthenia
gravis.41 Cancer was not overrepre- sented as a cause
of death in a Norwegian popu- lation-based study.36
Lymphomas have consistently been seen with a slightly
increased frequency in patients with myasthenia
gravis.42 Azathioprine used as immunosuppressive
treatment for myas- thenia did not influence the
general cancer risk in a Danish population study,43
whereas this treatment used for inflammatory
bowel disease slightly increased the cancer risk in a
similar Dutch study,44 and the risk of lip cancer also
increased with high-dose azathioprine.45
Treatment for myasthenia gravis can increase
the risk of coexisting disorders. Prednisolone
necessitates prophylaxis against osteoporosis, and
patients should be monitored for weight gain,
elevations in blood glucose levels, and hy-
pertension. Anticholinergic drugs for symptom- atic
treatment have transient and dose-limiting effects on
the autonomic nervous system.
Concomitant disease represents a major chal-
lenge in treating patients with myasthenia gra- vis. An
increasing number of patients are elderly, with
reduced mobility, respiratory function, and quality of
life due to the combined effects of several health
issues.
T HE R A p Y
DRUGS FOR S YMPTOMATic THERAPY
All subgroups of myasthenia gravis respond to
acetylcholinesterase inhibition (Fig. 1). Pyridostig-
mine is the preferred drug for the treatment of
symptoms in all myasthenia gravis subgroups2,11,12
NEJM.ORG DECEMBER 29, 2016
 M YASTHENIA G R AVIS
(Table 2). Neostigmine and ambenonium chloride are
also inhibitors of acetylcholinesterase but are less
effective than pyridostigmine in most pa- tients.
Increasing the release of acetylcholine
presynaptically by administering 3,4-diamino-
pyridine or ephedrine usually has a mild benefi- cial
effect, but it is rarely sufficient for practical use.
Myasthenia gravis with muscle-specific ki- nase
antibodies generally has a less favorable response
to drugs administered for symptomatic therapy than
do the other disease subgroups.23 Juvenile
myasthenia gravis often has an excellent response to
pyridostigmine.15,16 The dose of pyri- dostigmine is
decided on the basis of the effect on muscle
strength and dose-dependent side effects, most
frequently involving the gastroin- testinal tract.
Typical side effects are diarrhea, abdominal pain or
cramps, increased f latus, nausea, and increased
salivation, as well as uri- nary urgency and increased
sweating. Most pa- tients are capable of adjusting
their own dose, with possible variation from day to
day. The ef- fect of pyridostigmine remains
unchanged over a period of years. For patients who
have mild disease and nearly full remission with
symptom- atic therapy with drugs, no other drug
therapy is recommended (Fig. 3A).
IMMUNOSUPPRESSivE D RUG THERAPY
Most patients with myasthenia gravis need immu-
nosuppressive medication to meet the treatment goals
of full or nearly full physical function and high quality
of life. Immunosuppressive medica- tion is given to all
patients who do not have a fully satisfactory
functional result with symptom- atic and supportive
therapy alone. Expert con- sensus and data from
limited controlled trials support the use of
prednisone or prednisolone in combination with
azathioprine as first-line treat- ment.11,12,46 Prednisone
and prednisolone are re- garded as equally effective.
Alternate-day dosing, which is often used to reduce
the side effects of glucocorticoids, does not usually
lead to unwant- ed disease fluctuations, but the
evidence for re- duced side effects is weak.2 The
dose is usually increased gradually (up to 60 to 80
mg on alter- nate days) to avoid an initial
deterioration. After stable control of symptoms has
been achieved and the addition of other treatments
has further improved symptom control, the
glucocorticoid dose should be slowly reduced to the
lowest ef- fective level, which is often 10 to 40 mg
on al-
N ENGL J MED 375;26
ternate days. A major aim of treatment for ocu- lar
myasthenia gravis is to prevent generalization of the
disease. Retrospective and observational studies
strongly indicate that prednisolone mono- therapy
reduces this risk. Low-dose glucocorti- coid treatment
is therefore recommended by many experts for
patients with ocular myasthenia gravis who have
persistent symptoms and risk factors such as
detectable acetylcholine receptor antibodies, an
enlarged thymus,47 or results of neurophysiological
tests showing additional dis- ease involvement of
nonocular muscles.13,48,49
In most patients, azathioprine is added to
prednisolone because this combination provides a
better functional result with fewer side effects than
prednisolone monotherapy.50 If glucocorti- coids are
contraindicated or if the patient declines them,
azathioprine can be given alone. The rec- ommended
dose is 2 to 3 mg per kilogram of body weight.
Azathioprine inhibits purine syn- thesis and thus cell
proliferation, with a particu- larly strong effect on B
and T cells. Thiopurine methyltransferase activity
should be tested before treatment, if the test is
available, because low activity increases the risk that
azathioprine will have toxic side effects.51,52 Enzyme
activity is ab- sent in only 0.3% of the general
population, whereas low enzyme activity is found
in up to 10% of the population, with some variation
re- flecting genetic variants. Azathioprine is not rec-
ommended in patients with no thiopurine methyl-
transferase activity and should be used with
caution and only at a low dose in patients with low
activity. The effect of azathioprine on myas- thenic
weakness often takes months to appear, and patients
need to receive other immunosup- pressive
medication during this period. Long- term treatment
is safe in all patients, including those who are
young.43
Most guidelines recommend mycophenolate
mofetil for mild or moderate myasthenia gravis, even
though an additional benefit with this medi- cation
was not proven in two short-term pro- spective
studies, which had methodologic limi- tations.53-55 The
drug blocks purine synthesis and interferes with B-
cell and T-cell proliferation. Methotrexate,
cyclosporine, and tacrolimus are al- ternative secondary
immunosuppressive drugs.56-58 The effect of these drugs
is probably similar to that of azathioprine.
Rituximab represents a potentially potent treat-
ment for myasthenia gravis.59 This monoclonal
NEJM.ORG DECEMBER 29, 2016 2575
 25
76

N
NEJM.OR
2016

The New
England
Journal of
Medicine
Downloaded Table 2. Drugs Used Most Frequently for the Treatment of Myasthenia Gravis.
from Drug Mode of Action Dose Side Effects Risks and Contraindications
nejm.org at
TULANE Pyridostigmine Symptomatic; acetylcholinesterase Single dose: 10–120 mg; daily Cholinergic autonomic effects Cholinergic crisis
UNIV on inhibition dose: 40–600 mg
January 16, Prednisone or Immunomodulation Induction dose: 40–80 mg daily; Widespread dose-dependent glucocorticoid Gastrointestinal bleeding, cushingoid T
2019. For prednisolone stable dose: 5–20 mg daily; effects appearance he
personal use alternate-day treatment is an N
only. No alternative E
other uses Azathioprine Suppression of B and T cells 50–250 mg daily Nausea, vomiting, tiredness, infections, Leukopenia, liver toxicity W
without night sweats E
permission.
Mycophenolate mofetil Suppression of B and T cells 1.5–2 g daily Nausea, vomiting, diarrhea, joint pain, Leukopenia, progressive multifocal N
Copyright © infections, tiredness leukoencephalopathy; contraindi- cated GL
2016
during pregnancy
Massachusett A
s Medical Rituximab Suppression of B cells 0.5–1 g, repeated after 2 wk; can Nausea, infections, infusion-related Progressive multifocal leukoencepha- N
Society. All be repeated at 6-mo intervals problems lopathy
D
rights Methotrexate Inhibition of folate metabolism Gradual increase to 20 mg/wk Nausea, infections, lung disease Leukopenia, liver toxicity; contraindicat- JO
reserved. ed during pregnancy
U
Cyclosporine Suppression of T cells and natural 2.5–5 mg/kg of body weight daily Nausea, hypertension, infections, Kidney toxicity R
killer cells hypertrichosis
N
Tacrolimus Suppression of T cells and natural 3 mg daily Nausea, infections, lung disease, hyperten- Liver and kidney toxicity A
killer cells sion, neuropsychiatric problems
L
Cyclophosphamide Suppression of B and T cells 1–5 mg per kg administered by Nausea, vomiting, alopecia, discoloration Leukopenia of
intravenous infusion every 4 of nails and skin, infections M
wk for a limited period
Intravenous immune Suppression of B and T cells, 2 g per kg administered over a Nausea, headache, fever, hypotension or IgA deficiency, allergic reactions
globulin neutralization of autoantibodies period of 2 to 5 days hypertension, local skin reactions
 M YASTHENIA G R AVIS

A Proposed Treatment for Generalized Myasthenia Gravis B Proposed Treatment for Severe Exacerbations of Generalized
Myasthenia Gravis

Intensive care
Diagnosis confirmed
IV immune globulin or plasma exchange
Treatment of infection and other
precipitating events

Acetylcholinesterase inhibitor and

thymectomy (if early onset or thymoma)
Intensify long-
Improvement? Yes term
immuno-
Continue with suppression
Clinical remission? Yes acetylcholin-
esterase inhibitor No

No
Plasma exchange or IV immune globulin
Glucocorticoids in megadose
Intensive care
Prednisolone and azathioprine

Intensify long-
Continue with Improvement? Yes term
Adequate effect? Yes lowest immuno-
possible dose suppression

No No

Mycophenolate mofetil for mild Rituximab

or moderate symptoms Intensive care
Rituximab for severe symptoms Treatment of complications
Other immunosuppressive drugs Other immunosuppressive drugs
Never give up

Continue
Sufficient effect? Yes
treatment

No

Other immunosuppressive drugs

(methotrexate, cyclosporine, tacrolimus)
Reevaluation of diagnosis
Off-label drugs

Figure 3. Proposed Treatment Algorithms for Generalized Myasthenia Gravis and for Severe Exacerbations of Generalized Disease. Panel
A shows treatments for generalized myasthenia gravis, and Panel B shows treatments for severe exacerbations. Both algorithms are from
Gilhus and Verschuuren.2 IV denotes intravenous.

antibody binds specifically to the CD20 surface

have a substantial improvement with rituximab.60 A
antigen on B lymphocytes and should therefore be
recommended induction dose has not been
effective in antibody-mediated diseases such as
established. The treatment should be repeated if the
myasthenia gravis. T-cell responses are also
symptoms recur after several months. Con- cerns
influenced by rituximab. A group of experts who
regarding rituximab are the risk of pre- cipitating
recently issued guidelines for the management of
additional autoimmune disorders and JC virus–related
myasthenia gravis could not reach a consensus on the
progressive multifocal leukoen- cephalopathy. The
role of rituximab.11 Evidence from small case series
treatment scheme for general- ized myasthenia
indicates that two thirds of patients with severe
gravis is summarized in Fig- ure 3A.
myasthenia gravis and an insuffi- cient response to
prednisolone and azathioprine A number of monoclonal antibody drugs have

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The New England Journal of Medicine

Downloaded from nejm.org at TULANE UNIV on January 16, 2019. For personal use only. No other uses without permission.
Copyright © 2016 Massachusetts Medical Society. All rights reserved.
 T he NE W E NGL A ND JOU R NA L o f M E DICI NE
a proven effect in the treatment of other autoim- mune
disorders. They interfere with B cells, T cells,
complement, or other immunoactive elements.61,62
Formal evidence and cost–benefit information are
lacking for the use of these drugs in patients with
myasthenia gravis, although preliminary ob- servations
and mechanisms of drug action make several of them
promising alternatives. Autolo- gous hematopoietic
stem-cell transplantation was recently reported to
provide stable and treatment- free remission in seven
patients.63
Patients with myasthenia gravis that develops late or
is associated with thymoma or muscle- specific
kinase antibodies tend to have the most severe
disease and usually need long-term immu-
nosuppressive drug treatment, although some
patients with late-onset myasthenia gravis have
disease that is milder and more similar to early- onset
disease. The presence of antibodies against muscle-
specific kinase, titin, ryanodine receptor, or Kv1.4 is
an indication for immunosuppres- sion. Myasthenia
gravis associated with muscle- specific kinase
antibodies has a particularly fa- vorable response to
rituximab.
THYMEc TOMY
In patients with a thymoma and myasthenia gravis,
thymectomy should be performed to re- move the
tumor. A benefit after total thymec- tomy has been
reported for this subgroup; an even greater benefit
of total thymectomy has been reported for patients
with early-onset my- asthenia gravis without a
thymoma. The thymus has a key role in inducing
acetylcholine receptor antibody production in
patients with myasthe- nia gravis.64 Many studies
have compared the outcomes for patients who
undergo thymecto- my with the outcomes for those
who do not, and nearly all the studies have shown
a better outcome in the thymectomy group. 65,66 A
recent international, randomized, controlled trial involv-
ing 126 patients with early-onset or late-onset
myasthenia gravis confirmed a distinct benefit from
early thymectomy, supporting thymectomy in patients
with generalized disease, a disease duration of less
than 3 to 5 years, an age of less than 60 to 65 years,
and symptoms not fully relieved by
anticholinesterase drugs.67 Patients who underwent
thymectomy, as compared with those who did not
receive surgical treatment, had significant reductions
in symptoms, immunosup- pressive drug treatment, and
exacerbations dur-
2578
N ENGL J MED 375;26
ing 3 years of observation. The differences were
regarded as clinically meaningful. All thymic tissue
needs to be removed, including the tissue embedded
in mediastinal fat. Video- and robot- assisted methods
minimize the surgical proce- dure, are preferred by
most patients, and pro- vide the same benefit as
traditional open, transsternal thymectomy as long
as all tissue is removed.
Guidelines and consensus statements recom- mend
early thymectomy for patients with early- onset
myasthenia gravis.2,11,12 These patients most often have
thymic hyperplasia. Thymectomy should also be
considered in children.68 Most patients with late-
onset disease have an atrophic thymus.64 However,
thymic hyperplasia can occur in younger patients in
the late-onset subgroup. Thymectomy should also be
considered in patients with generalized myasthenia
gravis who have acetylcholine receptor antibodies
and whose symptoms developed at the age of 50 to 65
years,67 especially when the biomarkers show similari-
ties with early-onset disease. Current evidence does
not support thymectomy in patients with
myasthenia gravis and muscle-specific kinase or LRP4
antibodies.11 Thymectomy is also not rec- ommended
for patients with ocular myasthenia, since there is
insufficient evidence that surgery prevents
generalization or results in remission. However, it has
been argued that thymectomy should be considered
for the treatment of ocular myasthenia gravis when
drug treatment has failed, the patient has acetylcholine
receptor antibodies, and neurophysiological tests
indicate a risk of generalized disease.13
Thymectomy is usually not recommended for
patients in whom all muscle antibody tests are
negative. However, some of these patients have
acetylcholine receptor antibodies that are not
detected by routine assays. Therefore, in patients with
negative muscle antibody tests who have
generalized disease with biomarkers similar to those
in patients with early-onset disease, thymec- tomy may
be considered if the disease fails to respond to
immunosuppressive drugs.11
MYASTHENiA GRAVIS CRisis
Patients with worsening weakness who require
intubation or noninvasive ventilation should re- ceive
fast-acting immunosuppressive agents and intensive
care. An impending myasthenic crisis with rapid
worsening and severe weakness war-
NEJM.ORG DECEMBER 29, 2016
 M YASTHENIA G R AVIS

rants a similar intervention.69 The threshold for and this approach is preferable to withholding the
deciding to admit a patient to an intensive care unit drug altogether.
should be low. Increasing generalized weak- ness, Respiratory insufficiency due to diaphragmatic and
respiratory dysfunction, cardiac dysfunc- tion, severe intercostal muscle weakness is a major threat. Special
infection, and coexisting conditions are all relevant attention should be paid to respiratory function
factors to consider in making this decision. during any surgical procedure, including thymectomy, in a
Measures such as vital capacity and blood gas patient with myasthenia gravis. Optimal treatment of
levels have limited value, since deterioration can be all coexisting conditions is an important component of
rapid and unexpected as a result of the characteristic the management of myasthenia gravis. This can be a
myasthenic fatigability. Intravenous immune globulin particular chal- lenge in elderly patients with multiple
and plasma ex- change are regarded as equally coexisting conditions.
effective in treat- ing severe myasthenia gravis.70-72 Oral administration of pyridostigmine and
The choice be- tween them depends on individual prednisone or prednisolone is safe during preg-
patient factors and institutional experience, nancy.75,76 Current information indicates that
availability, and tradition. Intravenous immune treatment with azathioprine and cyclosporine is safe
globulin is often regarded as more convenient with as well. Mycophenolate mofetil and metho- trexate are
less severe side effects. A patient may have a contraindicated during pregnancy be- cause of
response to one treatment approach but not the teratogenic risks. Women are advised to avoid
other. The treatment effect is restricted to a period pregnancy for up to 1 year after finishing rituximab
of a few months and should therefore be combined treatment. Intravenous immune glob- ulin and plasma
with long-term immunosuppressive treatment. In some exchange are useful for worsen- ing weakness during
patients, the treatment response is delayed. Vig- orous pregnancy. Lactation should be encouraged. Transient
immunosuppressive treatment combined with intensive neonatal myasthenia occurs in 15% of children as a
care should be maintained as long as necessary to result of trans- placental IgG transfer of antibodies
induce remission. Myasthenic crisis with a need for against acetylcholine receptor, muscle-specific
respiratory support is now rare in patients with
kinase, or LRP4.76,77
myasthenia gravis, and mortality during myasthenic
crisis is also low.69 The treatment scheme for severe
exacerbations F U T U R E D I R E C T IONS
of myasthenia gravis is shown in Figure 3B.
With specialized treatment, the great majority
SuPPORTivE THERAPY AND MANAGEMENT of patients with myasthenia gravis do well. They are
able to perform daily tasks and maintain a near-
Physical activity and systematic training pro- grams normal quality of life. However, only a few patients
at a low or medium level of intensity should be have a full remission, and most do not even have a
recommended for patients with myas- thenia gravis full pharmacologic remission. Al- though the
and tailored to the individual pa- tient.2,11,12 Overweight disease-inducing antibodies have been characterized in
should be avoided. Assistive devices can be helpful with detail, the treatment is far from immunospecific. Data
ocular symptoms.13 Muscle relaxants, penicillamine, from prospective, blinded, controlled studies comparing
and some antibiotics (f luoroquinolones, macrolides, treatments are lack- ing, and there have been few
and aminoglycosides) should be avoided, if possible, in well-controlled studies of individual drugs and
patients with myasthenia gravis. Statins can aggravate nondrug inter- ventions. Apart from paraneoplasia
and unmask myasthenia gravis, but the presence of associated with thymoma, the causes of myasthenia
myasthenia gravis is not regarded as a gravis are unknown.
contraindication if statins are needed, and the Monoclonal antibodies have selective binding
indications for statin treatment in patients with and a high specificity regarding immunologic actions
myasthenia gravis are the same as the indications for but do not necessarily have any specific- ity for the
such treatment in patients without myasthe- nia treatment of myasthenia gravis. Ongo- ing trials are
gravis.73,74 If a drug appears to be indicated, vigilance evaluating more targeted immu- noactive therapy.
in looking for worsening of weakness is important Antigen-specific treatment is
when the new drug is introduced,

N ENGL J MED 375;26 NEJM.ORG DECEMBER 29, 2016 2579

 T he NE W E NGL A ND JOU R NA L o f M E DICI NE

being developed for myasthenia gravis associat- ed

with acetylcholine receptor, muscle-specific kinase,
and LRP4 antibodies, through interac- tion with
regulatory B or T cells.7,78,79
Even with today’s knowledge and available
treatments, it is a challenge to find the optimal
treatment for the individual patient. Specialized
diagnostic procedures and expert follow-up over time
improve treatment results. Standards and
possibilities for the diagnosis and treatment of
myasthenia gravis show great variation within and
between countries. Implementing best-prac- tice
standards universally represents a major chal- lenge.
This is especially important because my- asthenia
gravis is a potentially reversible disorder with
treatment options that can make a huge difference
for the patient.
No potential conflict of interest relevant to this article was
reported.

Disclosure forms provided by the author are available with the

full text of this article at NEJM.org.

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